Heterocyclic derivatives, pharmaceutical composition, pharmaceutical composition, intermediate compounds, methods of obtaining heterocyclic derivatives

 

(57) Abstract:

The invention describes new compounds of formula I

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their N-oxides, stereochemical isomeric forms and the pharmaceutically suitable salts accession acids, where a and b taken together form a bivalent radical of formula: -N=CH(a) -,- CH=N-(b), -CH=CH-(c), CH2-CH2(d), -C(= O)-CH2(e) -,- CH2-C(=O)-(f); R1is hydrogen; C1-6-alkyl or halogen; R2is hydrogen or halogen; R3is1-8-alkyl; C3-6-cycloalkyl or1-8-alkyl substituted by hydroxyl, exography; Het is a five - or desteklenen heterocyclic ring. Disclosed use as pharmaceuticals, in particular as agents to lower lipid levels, as well as pharmaceutical compositions and methods of making the compounds and compositions. 6 C. and 7 C.p. f-crystals, 15 PL.

The present invention concerns new compounds of formula (I), pharmaceutical compositions comprising these compounds, their production, and use as medicinal agents for the treatment of hyperlipidemia.

Over the last few years a wide recognition of acquired causal relationship between Ki-is barb (LDL) and very low density (VLDL) in the plasma, and premature atherosclerosis. Doctors and public consensus that the treatment of hypercholesterolemia brings therapeutic benefit. There are a limited number of drugs for the treatment of hyperlipidemia. The most important agents used for the treatment of hyperlipidemia include the biliary acids, fibrates (fibrates), nicotinic acid and inhibitors of HMG-CoA-reductase (hydroxymethylglutaryl-CoA-reductase). The disadvantage of introducing and gastrointestinal side effects available available sequestrants bile acid, cause a lot of problems. Fibrates have only limited applicability in the treatment of hypercholesterolemia certain types. The use of nicotinic acid causes side effects and problems associated with toxicity. Inhibitors of HMG-CoA-reductase already used for primary therapy of normal hypercholesterolemia. However, there is still a need for new agents that lower lipid levels, which are preferably operated by a mechanism that is different from the above-mentioned drugs. European patent EP-0,006,711-A, published September 9, 1980, discloses heterocyclic derivatives of (4-phenylpiperazin-1 - yl-relaxometer-1,3-dioxolane-2-and is distinguished from them by the presence of the sulfur atom, neighboring heterocycle (Het) and pharmacological profile, in particular their activity by inhibition of the synthesis of apolipoprotein Century, the Present invention provides new compounds of formula

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where A and B taken together form a bivalent radical of the formula

-N = CH- (a)

-CH= N - (b)

-CH= CH - (c)

-CH2-CH2(d)

-C(=O) - CH2) - (e)

-CH2- C(=0) - (f) in the bivalent radicals (a) and (b) the hydrogen atom may be substituted C1-6-alkyl; the bivalent radical (e) and (f) two hydrogen atoms may be substituted C1-6-alkyl;

R1is hydrogen, C1-6-alkyl or halogen;

R2is hydrogen or halogen;

R3is C1-6-alkyl;

C3-6-cycloalkyl; or C1-8-alkyl substituted by hydroxyl, exography; Het is a heterocycle selected from the group comprising pyridinyl; pyrimidinyl; pyrimidinyl, substituted with two substituents selected from C1-6-alkyl, amino; tetrazolyl, substituted C1-6the alkyl or aryl; triazolyl; triazolyl substituted by one or two substituents selected from C1-6-alkyl, trihalomethyl, hydroxyl, amino; thiadiazolyl, substituted C6-alkyl; N - oxide, stereochemical isomeric form or a pharmaceutically acceptable salt accession acid.

Preferred compounds where R1is chlorine or fluorine, as well as compounds in which R1is stands. Another preferred group are compounds in which the bivalent radical-A-B-, which is-N = CH - or-CH=N-, the hydrogen atom may be substituted C1-6- alkyl.

The following preferred group includes compounds in which R3is bootrom, Pentium or cyclopentyl.

A group of preferred compounds includes

CIS-4-[4-[4-[4-[[2-(4-chlorophenyl)-2-[[(4-methyl-4H-1,2,4-triazole-3-yl)thio] methyl] -1,3-dioxolane-4-yl] methoxy] phenyl]-1-piperazinil]phenyl]-2,4 - dihydro-2-(1-methylpropyl)-3H-1,2,4-triazole-3-one;

CIS-2-[4-[4-[4-[[2-(4-chlorophenyl)-2-[[4-methyl-4H-1,2,4-triazole - 3-yl)thio] methyl] -1,3-dioxolane-4-yl] methoxy] phenyl]-1 - piperazinil]phenyl]-2,4-dihydro-4-(1-methylpropyl)-3H-1,2,4 - triazole-3-one;

CIS-2-[4-[4-[4-[[2-(4-forfinal)-2-[[(4-methyl-4H-1,2,4-triazole-3-yl)thio] methyl] -1,3-dioxolane-4-yl] methoxy]phenyl]-1-piperazinil]phenyl] -4-cyclopentyl-2,4-dihydro-3H-1,2,4-triazole-3-one;

CIS-2-[4-[4-[4-[[2-(4-chlorophenyl)-2-[[(4-methyl-4H-1,2,4-triazole-3-yl) thio]methyl]-1,3-dioxole is(4-forfinal)-2-[[(4-methyl-4H - 1,2,4-triazole-3-yl)thio] methyl] -1,3-dioxolane-4-yl]methoxy]phenyl]-1 - piperazinil]-phenyl]-2,4-dihydro-3H-1,2,4-triazole-3-one;

and their pharmaceutically acceptable salts accession acid or a stereochemical isomeric form.

The above compounds possess the ability to inhibit apolipoprotein B.

Thus, the next aspect of the invention is a pharmaceutical composition having the ability to inhibit apolipoprotein B, including an active ingredient and a pharmaceutically acceptable carrier and as active ingredient containing compound 1 in a therapeutically effective amount.

The pharmaceutical composition can be obtained in the usual way.

The method of obtaining the pharmaceutical composition is a further object of the invention lies in that a therapeutically effective amount of compound 1 is thoroughly mixed with a pharmaceutically acceptable carrier.

Proposed in the invention compounds may be obtained from intermediates of General formula (III)

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or their salts accession acid or a stereochemical isomeric forms, where R1, R2and Het are as defined for compounds 1, a W is removed by a suitable group, such as halogen or sulfonyloxy.s (I), namely, that: O - alkylate intermediate product of the formula (II), where A-B and R3are as defined above intermediate product of the formula (III):

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in which R1, R2and Het are as defined above and W is a suitable leaving group such as halogen or sulfonyloxy, and do not necessarily translate compound of formula (I) into another compound 1 by transformation of functional groups; and/or, if desired, transfer the compound of formula (I) into a therapeutically active non-toxic salt accession acid or Vice versa, using alkali translate accession acid or Vice versa, using alkaline transfer salt accession acid in the form of a free base; and/or receive N-oxide or a stereochemical isomeric form.

Another alternative method of preparing compounds 1 is a method of obtaining lies in the fact that they are carrying out the reaction of the intermediate product of the formula (V) in which Het is as defined above with an intermediate product of the formula (IV) in which R1, R2, R3, -A-B - are as defined in paragraph 1, and W is a suitable removable group, such as halogen or sulfon transformation of functional groups; and/or, if desired, transfer the compound of formula (I) into a therapeutically active non-toxic salt accession acid or Vice versa, using alkaline transfer salt accession acid in the form of a free base; and/or receive N-oxide or a stereochemical isomeric form.

The above pharmaceutically acceptable salt accession acids include therapeutically active non-toxic form of salt accession acids, which are capable of forming compounds of formula (I). Salt can be obtained in the usual way by treating the basic form of a suitable acid.

Suitable acids include, for example, inorganic acid, such as halogen acids, e.g. hydrochloric or Hydrobromic acid; sulfuric; nitric; phosphoric acid and the like; or organic acids such as, for example, acetic, propionic, hydroxyestra, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methansulfonate, econsultancy, benzolsulfonat, paratoluenesulfonyl, ciclamino, salicylic, paraaminosalicilovaya, AMOVA and similar acids. As used above the term "salts is that they are solvate, for example, the hydrates, the alcoholate and the like. By treating the alkali salt form can be translated back into the form of a free base.

Used here above, the term "stereochemical isomeric form" defines all the possible isomeric forms, which can give the compound of formula (I). If not specifically mentioned or indicated, the chemical name of the compounds denotes the mixture of all possible stereochemical isomeric forms, and these mixtures containing all diastereomers and enantiomers of basic molecular structure. In more detail, stereospecific centers may have the R - or S-configuration; substituents on bivalent cyclic saturated radicals may have either the CIS-or TRANS-configuration. Obviously meant that the scope of this invention covers a stereochemical isomeric forms of the compounds of formula (I).

It is understood that the form of N-oxides of compounds of formula (I) include those compounds of formula (I) in which one or more atoms of nitrogen oxidized to the so-called N-oxide, particularly those N-oxides, in which the N-oxidized are one or more piperazinone of Izotov.

The substituents on the dioxolane part of the compounds of formulas is Horatio.

Preferred are also the compounds of formula (I), in which stereospecific carbon in the 2-position of the dioxolane part has S-configuration.

The compounds of formula (I) may also exist in tautomeric forms. For example, in tautomeric forms may exist such heterocycles as pyridine, pyrimidine, triazole, thiadiazole, oxadiazole, imidazole, thiazole and oxazole, which is substituted by hydroxyl, amino or C1-6-alkylaminocarbonyl. Although in the above formula is not explicitly specified, we mean that the scope of the present invention encompasses such forms.

As indicated above the compounds of formula (I) can be obtained by O-alkylation of phenols of the formula (II) derivatives of 1,3-dioxolane (III) in which W represents a suitable leaving group, such as, for example, chlorine or bromine or leaving sulfonyloxy, for example, 4-methylbenzenesulfonate group (tosylate) or methysulfonylmethane (mesilate).

The above reaction of O-alkylation is usually possible to carry out following known practice procedures, for example, by mixing and heating the reactants in a suitable solvent, such as bipolar aprotic solvent, aprigo metal, for example, sodium hydroxide or potassium hydroxide or carbonate of sodium or potassium.

Intermediates of formula (II) can be obtained in a similar manner as disclosed in the above-mentioned European patent EP-0006711. EP-0331232 published on 6 September 1989, and WO 93/19061, published on 30 September 1993, also reveal ways to obtain intermediates of formula (II).

The compounds of formula (I) can also be obtained by reaction of the intermediate product of formula (IV), in which, as defined here above, W is an appropriate leaving group, with a heterocyclic derivative of the formula (V).

The above reaction can be conducted by stirring and heating the intermediate product in a suitable solvent, such as bipolar aprotic solvent, e.g. N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide in the presence of such bases as a carbonate or hydroxide of an alkali metal, e.g. sodium carbonate or potassium or sodium hydroxide or potassium.

The compounds of formula (I) can also be translated one into the other. For example, compounds in which R3is1-8-alkyl substituted by hydroxyl, can be obtained by restoring the appropriate co (I), in which industrijski or ekzoticeski the nitrogen atom is not substituted. The compounds of formula (I) in which R3different from hydrogen, can be obtained known in the art by the reaction of N-alkylation of compounds of formula (I) in which R3is hydrogen.

The compounds of formula (I) can also be converted into the appropriate form N-oxides, through well-known specialists of the procedure for transfer of trivalent nitrogen in the form of N-oxide. Specified N-oksidirovanie can mainly be accomplished through the reaction of the educt of the formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, peroxides of alkali or alkaline earth metals, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may include peroxo acids, such as, for example, benzopyrenes-acid or halogen-substituted, benzopyrenes-acid, for example, 3-chlorobenzylamino-acid, paracalanidae acid, for example, purakayastha acid, alkylhydroperoxide, for example, tert-butylhydroperoxide. Suitable solvents are, for example, water; lower alcohols, e.g. ethanol and the, harmatan; and mixtures of such solvents.

Intermediates of formula (III), which are new, can be obtained by the following sequence of reactions. Perform S-alkylation of heterocyclic reagent (V) of the intermediate compound of formula (VI), where W is a suitable leaving group, as defined here above, with stirring and heating the intermediate product in a suitable reaction-inert solvent such as a ketone, for example acetone, in the presence of such bases as a carbonate or hydroxide of an alkali metal, e.g. sodium carbonate or potassium or sodium hydroxide or potassium. Then the resulting ketone of formula (VII) is transformed into the corresponding ketal formula (VIII) with stirring and heating the intermediate product of the formula (VII) with glycerol in the presence of acid, such as, for example, paratoluenesulfonyl, in a reaction-inert solvent such as toluene. In conclusion, hydroxypoly intermediate product of the formula (VIII) is converted into a suitable leaving group by means known in the practice of the reactions of transformation of functional groups, such as, for example, conversion of the hydroxyl in toilet by reaction with paradisum.

The intermediate product of the formula (VI) is converted into ketal, as described above. After that, the hydroxyl function is converted into a suitable leaving group, for example, sulfonyloxy. The reaction of the thus obtained intermediate (IX) with an intermediate product (II) results in an intermediate product (IV).

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Applying well-known specialists of the procedure, you can obtain a pure stereochemical isomeric forms of the compounds of formula (I). The diastereomers can be divided by physical methods division, such as selective crystallization or chromatography, for example, liquid chromatography". Enantiomers can be separated from each other by formation of diastereoisomeric salts with optically pure chiral acid and subsequent selective crystallization. These pure stereochemical isomeric form can also be obtained from the relevant stereochemical isomeric forms of the appropriate starting materials, providing stereospecifically the course of the reaction. If you want a specific stereochemical isomeric form, it is preferable to synthesize the specified form stereospecific methods of getting. As starting materials useful use is, the fact is evident from the results obtained in the Test for inhibition of apolipoprotein B (APO B), as described hereafter. Apolipoprotein B is the main protein component of very low density lipoproteins (VLDL) and low density lipoprotein (LDL). Approximately 60 to 70% of the total serum cholesterol is transported in LDL. The increased concentration of LDL cholesterol in serum is the cause of atherosclerosis. When the inhibition of the synthesis of apolipoprotein b reduces the amount of harmful low-density lipoprotein.

These connections do not have or does have a small unwanted side effects, such as, for example, activity in the inhibition of albumin activity inhibition of androgen biosynthesis or activity by inhibition of the biosynthesis of cholesterol.

From the point of view of its activity by inhibition of the synthesis of apolipoprotein B and activity reduction synthesis of related lipids present compounds are useful as medicines especially in the treatment of patients suffering from hyperlipidemia. In particular, these compounds can be used to produce drugs for the treatment is (LDL), and especially the damage caused by cholesterol associated with the specified VLDL and LDL. Hyperlipidemia may be caused by a large number of genetic and acquired diseases. They can be classified into primary and secondary gipolipidemicheskie state. The most common cases of secondary hyperlipidemia are diabetes mellitus, alcohol abuse, medications, hypothyroidism, chronic renal failure, nephrotic syndrome, cholestasis and bulimia. Primary hyperlipidemia are common hypercholesterolemia, familial combined hyperlipidemia, familial hypercholesterolemia, residual hyperlipidemia, chylomicronemia syndrome (chylomicronaemai syndrome), familial hypertriglyceridemia (hypertriglyceridaemia). These compounds can also be used for prophylaxis or treatment of patients suffering from atherosclerosis, especially coronary atherosclerosis, and more generally, from diseases associated with atherosclerosis, such as coronary heart disease, peripheral vascular disease, cerebral vascular disease. These compounds may cause regression of atherosclerosis and inhibit clinical consequences of atherosclerosis, in particular, pain is those compounds can be included in various pharmaceutical forms for administration to patients. For the preparation of such pharmaceutical compositions by mixing an effective amount of individual compounds in the form of a base or salt accession acid as the active ingredient with a pharmaceutically acceptable carrier. The specified media may be in various forms depending on the form required for drug administration. Preferably, such pharmaceutical composition was a uniform dosage form, preferably convenient for oral administration, rectal administration and parenteral injection. For example, upon receipt of the compositions in dosage forms for oral administration can be any pharmaceutical environment (such as, for example, water, glycols, oils, alcohols and the like), standard for orally applied liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, loosening agents and the like) for the case of production of powders, pills, capsules and tablets. Due to the easiness of taking tablets and capsules represent the most advantageous dosage forms for oral administration, in which, obviously, use the part sterile water, at least in the most part, although it may include other ingredients, for example, facilitate solubility. For example, it is possible to prepare solutions for injection, in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. You can also prepare a suspension for injection, in this case, you can use the appropriate liquid carriers, suspendresume agents and the like. In the compositions suitable for injection through the skin, carriers typically include an agent for increasing the permeability and/or a suitable wetting agent, usually combined with suitable additives of any nature in smaller quantities, these additives do not have a significant harmful impact on the skin. These supplements can facilitate application to the skin and/or may be useful in the preparation of the required compositions. Such compositions can be applied in various ways, for example, in the form of plaques, patches, ointments, transdermal administration. It is obvious that salt accession acid compounds of the formula (I), due to the increased solubility compared to the respective basic form, more suitable for the preparation of aqueous compositions. For promposal in a standard dosage forms. Used in this description, the term "standard dosage form" refers to a discrete unit suitable for standardized dosages, each unit contains a predetermined quantity of active ingredient calculated with the purpose of works of the desired therapeutic effect, in Association with a suitable pharmaceutical carrier. Examples of such dosage forms are tablets (including scored tablets or in the shell), capsules, pills, sachet powders, pills, solutions or suspensions for injection, a volume equal to a teaspoon, a volume equal to a tablespoon, and the like and their individual sets.

Experts in the field of therapy hyperlipidemia can easily determine the effective daily amount on presents here the results of the tests. Basically it is assumed that a therapeutically effective dose should be from 0.001 to 5 mg/kg body weight, more preferably from 0.01 mg/kg to 0.5 mg/kg of body weight. Suitable option could be the introduction of a therapeutically effective dose for two, three, four or more doses per day (subdata) with suitable time intervals. These subdata can be a standard lekarstwo dosage form.

As is well known in the art, the exact dosage and frequency of administration depend on the particular used the compounds of formula (I), the specific conditions of treatment, the severity of the condition to be treated, age, weight and General physical condition of the particular patient, and on the possible reception of other medicines. Moreover, it is clear that the effective daily amount can be reduced or increased depending on the patient's response and/or depending on the evaluation of the physician prescribing the compounds of the present invention. Consequently, listed here above interval for the effective daily amount is only indicative.

Experimental part

Here the designation "DIPE" refers to diisopropyl ether, "MICK" means methylisobutylketone and "DMF" means N,N-dimethylformamide.

A. Obtaining an intermediate product

Example 1.

a) a Mixture of 1-methyl-1H-1,2,4-triazole-5-thiol (35 g), 2-chloro-1-(forfinal)-ethanone (51,4 g) and sodium carbonate (32,5 g) in 2-propanol (500 ml) is stirred and heated under reflux for 4 hours. The solvent is evaporated, the residue dissolved in CH2Cl2filter and filtermaterial on silica gel (eluent CH2Cl2/CH3OH = 99/1). Pure fractions are collected and evaporated. The residue is crystallized from DIPE, getting 1-(4-forfinal)-2-[(2-methyl-2H-1,2,4-triazole-3-yl)thio]alanon (intermediate 1).

b) a Mixture of intermediate (1) (22 g), glycerol (to 39.6 g) and paratoluenesulfonyl (20 g) in toluene (200 ml) is stirred at reflux over night. The mixture is cooled and water is added. The mixture is extracted with toluene and washed with water. The organic layer is dried, filtered and the solvent evaporated. The residue is cleaned by a method of high performance liquid chromatography on silica gel (eluent CH2Cl2/CH3OH=98/2). Pure fractions are collected and evaporated, receiving 9 g (31,6%) ()CIS-2-(4-forfinal) -2-[[(2-methyl-2H-1,2,4-triazole-3-yl)thio] methyl] -1,3-dioxolane-4-methanol (intermediate 2).

C) a Mixture of intermediate 2 (9 g), paratoluenesulfonyl (6.3 g) and N,N-dimethyl-4-pyridylamine (1 g) in CH2Cl2(150 ml) and N,N-diethylethanamine (5 ml) was stirred at room temperature for 4 hours. Add water and separate the layers. The organic layer was washed with water, dried, filtered and the solvent evaporated. The remainder of the cleaning column chromatography on silica gel (eluent CH2t MICK and transferred to salt paratoluenesulfonyl (1:1). Add a little DIPA and the product is planted in the form of crystals. The precipitate is filtered off and dried, obtaining 6.8 g (37.8%) {()-CIS-2-(4-forfinal)-2-[[(2-methyl-2H-1,2,4-triazole-3-yl)thio] methyl]-1,3-dioxolane-4-methanol}-4-methylbenzenesulfonate 4-methylbenzenesulfonate (1:1) (intermediate 3). Similarly also receive:

{()-CIS-2-(4-forfinal)-2-[[(4-methyl-4H-1,2,4-triazole-3-yl)- thio]methyl] -1,3-dioxolane-4-methanol} -4-methylbenzenesulfonate (ester) 4-methylbenzenesulfonate (1:1) so pl. to 136.4oC (intermediate 4);

{()-CIS-2-(2,4-differenl)-2-[[(4-methyl-4H-1,2,4-triazole-3-yl) thio]methyl] -1,3-dioxolane-4-methanol} -4-methylbenzenesulfonate (ester) 4-methylbenzenesulfonate (1:1) (intermediate 5);

{ ()-TRANS-2-(4-chlorophenyl)-2-[[(4-methyl-4H-1,2,4-triazole-3-yl) thio]methyl] -1,3-dioxolane-4-methanol} -4-methylbenzenesulfonate (ester) 4-methylbenzenesulfonate (1:1) so pl. 151,9oC (intermediate 6);

{()-CIS-2-(2,4-differenl)-2-[[(2-methyl-2H-1,2,4-triazole-3-yl) thio]methyl] -1,3-dioxolane-4-methanol} -4-methylbenzenesulfonate (ester) (intermediate 7); and

{ ()-CIS-[2-(methyl bromide)-2-(2,4-differenl)-1,3-dioxolane-4-yl] methyl} -2-naphthalenesulfonate (intermediate 40).

Example 2.

a) a Mixture of 2-bromo-1-(4-chlorophenyl)ethanone (350 g), glycerol (322 g) and passes using a water separator. The reaction mixture was poured into an aqueous solution of NaHCO3stirred for some time. The organic layer is separated, dried, filtered and the solvent is evaporated, getting 485 g (93% oil) (CIS+TRANS)-2-(methyl bromide)-2-(4-chlorophenyl)-1,3-dioxolane-4-methanol (intermediate product 8a). To a mixture of intermediate 8a (25 g) and N,N-dimethyl-4-pyridylamine (1 g) in N, N-diethylethanamine (25 ml) and CH2Cl2(250 ml) portions add 2-naphthalenesulfonate (21 g) and the mixture is stirred at room temperature for 2 hours. The mixture was poured into water and washed. The organic layer is dried, filtered and the solvent evaporated. The remainder of the cleaning column chromatography on silica gel (eluent CH2Cl2/CH3OH=99/1). Pure fractions are collected and evaporated. The remainder of the cleaning column chromatography (eluent CH2Cl2, /hexane from 40/60 to 60/40). Pure fractions are collected and evaporated, receiving the output of 21.8 g (55%) {()-CIS-[2-(methyl bromide) -2-(4-chlorophenyl)-1,3-dioxolane-4-yl]methyl} 2-naphthalenesulfonate (intermediate product 8b).

C) 2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinil] phenyl]-2-(1-methylpropyl)-3H-1,2,4-triazole-3-one (206,9 g) are added to a solution of the intermediate product (8b) (250 g) dimethyls the Oh temperature. The mixture was poured into water (3000 ml) and stirred for 30 minutes. The precipitate is filtered off, washed with 2-propanol (1000 ml) and DIPA (1000 ml), then dried, receiving the output 316 g (92.2 per cent) (a)-CIS-4-[4-[4-[4-[[2-(methyl bromide)-2-(4-chlorophenyl)-1,3 - dioxolane-4-yl] methoxy]phenyl]-1-piperazinil]phenyl]-2,4-dihydro - 2-(1-methylpropyl)-3H-1,2,4-triazole-3-one (intermediate product 8c).

Similarly get:

B. Obtain the target compounds

Example 3. A mixture of 4-methyl-4H-1,2,4-triazole-3-thiol (1.9 grams), intermediate (8C) (9 g) and sodium carbonate (3 g) in DMF (150 ml) is stirred under N2if 120oC during the night. The mixture is cooled, diluted with water, the product precipitates as a crystalline precipitate. The precipitate is filtered and cleaned column chromatography on silica gel (eluent CH2Cl2/n-hexane/EtOAc/ /CH3OH= 500/250/250/2). Clean fractions are collected and evaporated. The residue is triturated in CH3HE and recrystallized from n-C4H9OH, receiving the output of 6.3 g ()-CIS-4-[4-[4-[4-[[2-(4-chlorophenyl)-2-[[4-methyl - 4H-1,2,4-triazole-3-yl)thio]methyl]-1,3-dioxolane-4 - yl] methoxy] phenyl]-1-piperazinil]phenyl]-2,4-dihydro-2- (1-methylpropyl)-3H-1,2,4-triazole-3-one (68%); so pl. 173oC (compound 22).

Example 4. A mixture of intermediate (3) (3.3 grams), 2,4-dihydro-2-[4-ml) is stirred at room temperature under N2within 6 hours. To the mixture add another intermediate product (3) (1 g) and stirred for 1 hour. The mixture was poured into water and filtered. Sediment clean column chromatography on silica gel (eluent CH2Cl2/CH3OH= 99/1). Pure fractions are collected and evaporated. The residue is crystallized from MICK, receiving the output of 1.6 g of ()-CIS-2-[4-[4-[4-[[2-(4-forfinal)-2-[[2-methyl-2H-1,2,4-triazole-3-yl) thio] methyl] -1,3-dioxolane-4-yl] methoxy] -phenyl] -1-piperazinil] phenyl] -2,4 - dihydro-4-(1-methylpropyl)-3H-1,2,4-triazole-3-one (45.7%); so pl. 157,3oC (compound 70).

Example 5. Sodium hydride, 50% dispersion in mineral oil (0.31 g), add to the mixture of compound (76) (4.3 g) in DMF (100 ml) and the mixture was stirred at room temperature for 30 minutes. Add 2-bromopropane (0,86 g) and the mixture is stirred at room temperature for 48 hours. Again add sodium hydride, 50% dispersion in mineral oil, and 2-bromopropane and the mixture is stirred for 4 hours. The mixture was poured into water, extracted with CH2Cl2and washed with water. The organic layer is dried, filtered and the solvent evaporated. The remainder of the cleaning column chromatography on silica gel (eluent CH2Cl2/CH3OH= 99/1). Pure fractions are collected and evaporated. The rest of cccii collected and evaporated. Fraction 1 is crystallized from n-C4H9OH, receiving the output of 0.4 g of ()-CIS-4-[4-[4-[4-[[2-(4-chlorophenyl)-2-[[[1-(1-methylethyl) -1H-1,2,4-triazole-3-yl]thio]methyl]-1,3-dioxolane-4-yl]methoxy] phenyl]-1 - piperazinil]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazole - 3-one; so pl. of 128.8oC (compound 112). Fraction 2 pound in CH3HE, receiving the output of 1.4 g of ()-CIS-4-[4-[4-[4-[[2-(4-chlorophenyl)-2-[[[2- (1-methylethyl)-2H-1,2,4-triazole-3-yl] thio] methyl]-1,3 - dioxolane-4-yl]methoxy]phenyl]-1-piperazinil] phenyl] -2,4-dihydro-2- (1-methylpropyl)-3H-1,2,4-triazole-3-one; so pl. 141,2oC (compound 82).

Example 6. A solution of sodium borohydride (1 g) in water (20 ml) is added drop by drop to a solution of compound (47) (3.6 g) in DMF (100 ml). The reaction mixture was stirred over night at room temperature. Add acetic acid (1 ml). Add water (750 ml), resulting in crystallization of the product. The residue is cleaned by way of column chromatography on silica gel (eluent CH2Cl2/CH3OH=90/10). Pure fractions are collected and the solvent evaporated. The residue is triturated in 2-propanol. The precipitate is filtered off and dried, obtaining a yield of 2.9 g of ()-CIS-4-[4-[4-[4-[[2-(4-chlorophenyl)-2-methyl-4H-1,2,4-triazole-3-yl) thio] methyl]-1,3-dioxolane-4-yl]methoxy]phenyl]-1-piperazinil] phenyl]-2,4 - dihydro-2-(2-hydroxy-1-METI the EP 7:

Test for inhibition of apolipoprotein B (apo B)

The cultured cells human liver (G2-cells, which synthesize and secrete low-density lipoprotein, incubated over night at 37 oC in liquid medium containing radioactively labeled lecithin. Thus radioactively labeled lecithin include apolipoprotein B. the Liquid medium is decanted and secrete apolipoprotein B by double immunosurgery, namely, first to the liquid medium was added specific for apolipoprotein B antibody (antibody1), and then add the second antibody (antibody2), which are specifically attached to the complex apoB-antibody1. The so formed complex apoB-antibody1-antibody2deposited, and select by centrifugation. The number of synthesized during the night apolipoprotein B receive measuring the radioactivity of the selected set. To measure the inhibitory activity of the compounds investigated this connection is added to the liquid medium in various concentrations and compare the concentration of apolipoprotein B, synthesized in the presence of the compounds (concentration of apoB (Pius apoB (control)). For each experiment, the inhibition of the formation of apolipoprotein B is expressed as follows: %inhibition=100(1-conc.apoB (after)/conc.apoB (control)).

After conducting several experiments with the same concentration calculating the mean value of inhibition for these experiments. Calculate the value of the IC50(the concentration of drug needed to reduce the allocation of apoB 50% of control values).

In table. 13 shows the IC50-values for some compounds of formula (I). The compounds of formula (I), not listed in table 13, but for which there are relevant data have IC50value 110-6M or more.

, Examples of compositions

The following preparative forms are typical pharmaceutical composition in the form of standard (single) dose, appropriate for General or local application to warm-blooded animals in accordance with the present invention.

Used in these examples, the term "active ingredient" (AI) refers to the compound of formula (I), form N-oxide, its pharmaceutically acceptable salt accession acid or its stereochemical isomeric form.

Pria dissolved in 4 l of boiling purified water. In 3 l of this solution are dissolved first 10 g of 2,3-hydroxybutanoic acid and then 20 g AI. The latter solution is combined with the remaining part of the previous solution and add 12 l 1,2,3-propanetriol and 3 l of 70% solution of sorbitol. 40 g Matricaria (sodium saccharin) dissolved in 0.5 l of water and add 2 ml of raspberry essences and 2 ml essences gooseberry. The latter solution is combined with the previous one, add q water.s. up to a volume of 20 l, obtaining a solution for oral administration, comprising 5 mg AI on a teaspoon (5 ml). The resulting solution fill in the appropriate containers (tanks).

Example 9:

Capsules

Vigorously mix 20 g AI, 6 g of lauryl sodium, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide, and 1.2 g of magnesium stearate. Then the mixture fill 1000 suitable hardened gelatin capsules, each containing 20 mg of AI.

Example 10:

Coated tablet

Preparation of core tablets. Well mix 100 g AI, 570 g lactose and 200 g starch and then the mixture is moistened with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone (Kollidon - K90) in about 200 ml of water. Wet powder mixture is sieved, dried and sieved again. Then peremeshivayte and pressed tablets, getting 10,000 tablets each containing 10 mg of active ingredient.

The sheath. To a solution of 10 g of methyl cellulose (Methocel 60HG) in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose (Ethocel 22 cps) in 150 ml of dichloromethane. Then add 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. The last solution is added to the previous one and then add 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated colour suspension (Opaspray K-1-2109), the resulting mixture is homogenized. The core tablets cover the thus obtained mixture in the coating.

Example 11:

Solutions for injection

1.8 g of methyl-4-hydroxybenzoate and 0.2 g of propyl-4-hydroxybenzoate dissolved in about 0.5 l of boiling water for injection. After cooling to approximately the 50oC added while stirring 4 g lactic acid, 0.05 grams propylene glycol and 4 g of AI. The solution is cooled to room temperature and diluted with water q. s. for injection to a volume of 1 l, obtaining a solution containing 4 mg AI on the ml Solution is sterilized by filtration (USP U. S. P.) XVII p. 811) and fill them sterile containers.

< / BR>
Compound 139 (0,0027 mol) is stirred in boiling 2-propanol (20 ml). HCl added to 2-propanol (5 ml) dropwise. There is a complete dissolution. The mixture is allowed to cool to room temperature, and crystallization occurs. The precipitate is filtered off, stirred in 2-propanol, filtered off, then dried, earn 1.25 g of compound 137 in the form of its HCl (1: 3)H2O (1:1) salt, representing the connection 139, having the structure:

< / BR>
Stereochemistry: (2S - ClS)

The salt form: hydrochloride (1:3) hydrate (1:1)

In table. 14 and 15 presents the physico-chemical constants of compounds that have not been previously characterized.

In table. 14 presents the results of elemental analysis; presents both theoretical (column"]. ") and experimental (column "experimental. ") data. In table. 15 presents data on mass spectrometry, the molecular ion and the base peak.

1. Heterocyclic derivatives of General formula 1

< / BR>
where a and b taken together form a bivalent radical of formula:

-N=CH- (a)

-CH=N - ()

-CH-CH- (c)

-CH2=CH2(d)

-C(=O)-CH2) (e)

-m; in the bivalent radical (e) and (f) two hydrogen atoms may be substituted C1-6-alkyl; R1is hydrogen, C1-6-alkyl or halogen; R2is hydrogen or halogen; R3is C1-8-alkyl, C3-6-cycloalkyl; or C1-8-alkyl substituted by hydroxyl, exography; Het is a heterocycle selected from the group comprising pyridinyl; pyrimidinyl; pyrimidinyl, substituted with two substituents selected from C1-6-alkyl, amino; tetrazolyl, substituted C1-6the alkyl or aryl; triazolyl; triazolyl substituted by one or two substituents selected from C1-6-alkyl, trihalomethyl, hydroxyl, amino; thiadiazolyl, substituted C1-6-alkyl; thiazolyl; oxazolyl, substituted C1-6-alkyl; imidazolyl, imidazolyl, substituted C1-6-alkyl; N-oxide, stereochemical isomeric form or a pharmaceutically acceptable salt accession acid.

2. Connection on p. 1, in which R1is chlorine or fluorine.

3. Connection on p. 1, in which R1is stands.

4. The compound according to any one of paragraphs.1 to 3, in which the bivalent radical-And-In-which-N= CH - or-CH= N-, the hydrogen atom by bootrom, Pentium or cyclopentyl.

6. Connection on p. 1 representing: CIS-4-[4-[4-[4-[[2-(4-chlorophenyl)-2-[[(4-methyl-4H-1,2,4-triazole-3-yl)thio]methyl]-1,3-dioxolane-4-yl] methoxy] phenyl] -1-piperazinil] phenyl] -2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazole-3-one; CIS-2-[4-[4-[4-[[2-(4-chlorophenyl)-2-[[(4-methyl-4H-1,2,4-triazole-3-yl)thio] methyl] -1,3-dioxolane-4-yl] methoxy]phenyl]-1-piperazinil] phenyl] -2,4-dihydro-4-(1-methylpropyl)-3H-1,2,4-triazole-3-one; CIS-2-[4-[4-[4-[[2-(4-forfinal)-2-[[(4-methyl-4H-1,2,4-triazole-3-yl)thio] methyl] -1,3-dioxolane-4-yl] methoxy] phenyl] -1-piperazinil]phenyl]-4-tiopental-2,4-dihydro-3H-1,2,4-triazole-3-one; CIS-2-[4-[4-[4-[[2-(4-chlorophenyl)-2-[[(4-methyl-4H-1,2,4-triazole-3-yl)thio] methyl] -1,3-dioxolane-4-yl]methoxy]phenyl]-1-piperazinil] phenyl] -2,4-dihydro-4-pentyl-3H-1,2,4-triazole-3-one; CIS-4-(1-ethylpropyl-2-[4-[4-[4-[[2-(4-forfinal)-2-[[(4-methyl-4H-1,2,4-triazole-3-yl)thio]methyl]-1,3-dioxolane-4-yl]methoxy]phenyl]-1-piperazinil]phenyl]-2,4-dihydro-3H-1,2,4-triazole-3-one; and pharmaceutically acceptable salts accession acid or a stereochemical isomeric form.

7. Connection PP.1 - 6, with apolipoprotein B-inhibitory activity.

8. Pharmaceutical composition having apolipoprotein B-inhibitory activity, comprising the active ingredient and the pharmaceutical is PP.1 - 6 in therapeutically effective amounts.

9. A method of obtaining a pharmaceutical composition according to p. 8, characterized in that a therapeutically effective amount of a compound according to any one of paragraphs.1 - 6 thoroughly mixed with a pharmaceutically acceptable carrier.

10. The intermediate product of General formula III

< / BR>
his salt accession acid or a stereochemical isomeric form, where R1, R2and Het are as defined in paragraph 1, and W is a suitable leaving group such as halogen or sulfonyloxy.

11. A method of obtaining a heterocyclic derivative of the formula I on p. 1, characterized in that the O - alkylate intermediate product of the formula II, where a-b and R3are as defined in paragraph 1, the intermediate product of the formula III

< / BR>
in which R1, R2and Het are as defined in paragraph 1, and W is a suitable leaving group such as halogen or sulfonyloxy, and do not necessarily translate compound of formula I into another compound 1 by transformation of functional groups; and/or, if desired, transfer the compound of formula I in a therapeutically active non-toxic salt accession acid or naoborot stereochemical isomeric form.

12. A method of obtaining a heterocyclic derivative of the formula I on p. 1, characterized in that conduct the reaction intermediate product of the formula V, in which Het is as defined in paragraph 1, with an intermediate product of the formula IV in which R1, R2, R3-And-B - are as defined in paragraph 1, and W is a suitable leaving group such as halogen or sulfonyloxy;

< / BR>
and do not necessarily translate compound of formula I into another compound I by transformation of functional groups; and/or, if desired, transfer the connection of form I in a therapeutically active non-toxic salt accession acid or Vice versa, using alkaline transfer salt accession acid in the form of a free base; and/or receive N-oxide or a stereochemical isomeric form.

13. Connection on p. 1, representing the (-)-[2S-[2,4(S*]]-4-[4-[4-[4-[[2-(4-chlorophenyl)-2-[[(4-methyl-4H-1,2,4-triazole-3-yl)thio] methyl] -1,3-dioxolane-4-yl] methoxy] phenyl] -1-piperazinil]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazole-3-one or its pharmaceutically acceptable salt accession acid.

Priority points and features:

19.10.95 under item 3 and N-oxide compounds on p. 1;

27.10.94 under item 1, CR

 

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The invention relates to ether compounds and their use

The invention relates to derivatives of 3-(piperidinyl-1)-chroman-5,7-diol and 1-(4-hydroxyphenyl)-2-(piperidinyl-1)alkanol General formula I or their pharmaceutically acceptable salts accession acid, in which (a) R2and R5taken individually and R1, R2, R3and R4independently represent hydrogen, (C1-C6)-alkyl, halogen, HE or or7and R5represents methyl; or (b) R2and R5taken together form a ring chroman-4-ol, a R1, R3and R4each independently represent hydrogen, (C1-C6)-alkyl, halogen, HE or or7; R7represents methyl; and R6represents a substituted piperidinyl or 8-azabicyclo[3,2,1]octenidine derived; provided that (a) if R2and R5taken separately, at least one of R1, R2, R3and R4is not hydrogen; and (b) if R2and R5taken together, at least one of R1, R3and R4is not hydrogen, with the property that the NMDA antagonist

The invention relates to new fluorine-containing organic compounds, more specifically to an amine derivative having biological activity

The invention relates to new derivatives of piperidine and piperazine of the formula I

< / BR>
where Ind is unsubstituted or one - or twofold substituted by Oh, OA, CN, Hal, COR2or CH2R indol-3-ilen balances;

R1is unsubstituted or once substituted with CN, CH2OH, CH2OA or COR2benzofuran-5-yl, 2, 3-dihydrobenzofuran-5-yl-, chroman-6-yl, chroman-4-one-6-yl, 3-chromen-6-yl or chromen-4-one-6-yl;

Q-CmH2m;

Z is N or CR3;

A is alkyl with 1-6 C-atoms;

Hal is F, Cl, Br or I;

R2-OH, OA, NH2, NHA or NA2;

R3Is H, OH or OA;

m is 2, 3 or 4,

and their physiological acceptable salts

The invention relates to the field of organic chemistry and pharmaceuticals, namely heterobicyclic compounds and pharmaceutical compositions based on them, as well as methods of producing these compounds

The invention relates to stereoisomerism forms of Itraconazole (X=CL) and saperconazole (X= F), which can be represented by the formula CIS-(I) that are listed in the text of the description, their pharmaceutically acceptable acid additive salt forms, and methods of producing these stereoisomeric forms and their complexes with cyclodextrin derivatives and pharmaceutical compositions containing the above-mentioned complexes with anti-fungal activity

The invention relates to piperazine derivatives or its salts, which are used as therapeutic agents for diseases of the circulatory organs and areas of the brain

The invention relates to vasoconstrictor /(benzodioxan, benzofuran and benzopyran)-alkylamino/-alkyl-substituted guanidine formula I, their pharmaceutically acceptable salts, or their stereochemical isomers, where X = O, CH2or a direct bond; R1= H, C1-C4alkyl, R2= H, C1-C6alkyl, C3-C6alkenyl, C3-C6quinil, R3= H, C1-C4alkyl; or R2and R1taken together, may form a bivalent radical of the formula/CH2/m-, where m = 4 or 5; or R1and R2taken together may form a bivalent radical of formula-CH=CH -, or the formula/CH2/n-, where n = 2, 3 or 4; or R3may indicate a relationship when R1and R2taken together form a bivalent radical of formula-CH=CH-CH= -, -CH= CH-N= or-CH=N-CH=; where one or two hydrogen atom substituted by a halogen atom, a C1-C6alkoxygroup, C1-C6the alkyl, CN, NH, mono - or di(C1-C6alkyl) amino group, aminocarbonyl, C1-C6alkylaminocarbonyl, R4-H or C1-C6-alkyl; Alk1denotes a divalent C1-C3-ascandilwy radical, A denotes dwuhvalentny a radical of the formula /, lk2represents C2-C15-alcander or C5-C7-cycloalkenyl, and each "R" represents 0, 1, 2, R7and R8each independently is H, a halogen atom, a C1-C6by alkyl, hydroxyl, C1-C6allyloxycarbonyl, C1-C6alkoxygroup, cyano, amino, C1-C6the alkyl, carboxyla, nitro or amino group, aminocarbonyl, C1-C6alkylcarboxylic or mono - or di-(C1-C6)alkylamino, provided that excluded /2-/ (2,3-dihydro-1,4-benzodioxin-2-yl)-methyl/-amino/-ethyl-guanidine

The invention relates to 2,3-dihydro-1,4-benzodioxin-5-yl-piperazinyl derivative of the formula I, where R1denotes halogen, lower alkyl or alkoxyl, or cyano; m = 1 or 2, n = 0 or 1, And - Allenova chain with 2 to 6 carbon atoms which may be substituted by one or two lower alkyl groups or one phenyl group; B is methylene, ethylene, carbonyl, sulfinil, sulfonyl or sulfur, or their salts with 5-HTIA-antagonistic activity
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