Derivatives cycloalkane-indole and azaindole, mixture of isomers, or individual isomers and their pharmaceutically acceptable salts, derivatives of carboxylic acid as starting compounds and pharmaceutical composition inhibiting the release associated with apolipoprotein b-100 lipoproteins

 

(57) Abstract:

Describes the new derivatives cycloalkane-indole and azaindole, mixture of isomers, or individual isomers of General formula I, their pharmaceutically acceptable salts, in which R1and R2along with connecting them to a double bond means phenyl or peregrinae ring or a ring of formula (A), in which R8is hydrogen, C1-C4-alkyl; R1, R4along with connecting them to a double bond means a phenyl ring or a four to eight-membered cycloalkenyl balance, and specified for R1/R2and R3/R4ring unsubstituted or substituted by 1 to 3 identical or different substituents selected from the group including CF3C1-C6alkoxy, C1-C6alkoxycarbonyl, C1-C6alkyl, possibly substituted by a hydroxy-group; D is hydrogen, C4-C12cycloalkyl, C1-C12alkyl; E is a group WITH or CS; L Is O, S, - NR9; R9is hydrogen, C1-C6alkyl, possibly substituted by phenyl, hydroxy; R5is phenyl, pyridyl, thienyl, possibly substituted, R6- hydrogen, carboxypropyl, C1-C5alkoxycarbonyl, C1-C6alkyl, possibly substituted, hydroc the sludge; R7is hydrogen, R6and R7together mean a group of the formula =O; describes also intermediate compounds, inhibiting the release associated with apolipoprotein B-100 lipoproteins pharmaceutical composition. 3 S. and 2 C.p. f-crystals, 35 PL.

The invention relates to new nitrogen-containing heterocyclic compounds which possess valuable biological properties, in particular derived cycloalkane-indole-azaindole, mixtures of their isomers, or individual isomers and their pharmaceutically acceptable salts, derivatives of carboxylic acid as starting compounds and pharmaceutical compositions inhibiting the release associated with apolipoprotein B - 100 lipoproteins.

From application EP N 0234708 known derivatives cycloalkane - indole-azaindole having biological activity, for example, inhibiting the release associated with apolipoprotein B-100 lipoprotein activity.

Object of the invention is the expansion of the range derived cycloalkanones and-azaindole possessing biological activity, in particular inhibiting the release associated with apolipoprotein B-100 lipoprotein activity of formula (I)

< / BR>
in which R1and R2along with connecting them to a double bond means phenyl or peregrinae ring or a ring of the formula

< / BR>
in which

R8means hydrogen or an unbranched or branched alkyl with 1 to 4 carbon atoms,

R3and R4along with connecting them to a double bond means a phenyl ring or a four - to eight-membered cycloalkenyl balance, and specified for R1/R2and R3/R4ring unsubstituted or substituted by 1 to 3 identical or different substituents selected from the group comprising trifluoromethyl, unbranched or branched alkoxy group with 1 to 6 carbon atoms, unbranched or branched alkoxycarbonyl with 1 to 6 carbon atoms in the CNS part, unbranched or branched alkyl with 1-6 carbon atoms, unsubstituted or substituted by hydroxy group,

D is hydrogen, cycloalkyl with 4-12 carbon atoms, or an unbranched or branched alkyl with 1-12 carbon atoms,

E - group-CO - or - CS-,

L - atom oxygen, sulfur or the group-NR9in which R9means hydrogen or an unbranched or branched alkyl with 1-6 carbon atoms, unsubstituted or someseni is new or different substituents, selected from the group comprising nitro group, carboxy group, halogen, an unbranched or branched alkoxycarbonyl with 1-6 carbon atoms in the CNS part, unbranched or branched alkyl with 1-6 carbon atoms, unsubstituted or substituted by hydroxy group, and/or a group of the formula - OR10or-NR11/R12in which R10means hydrogen or an unbranched or branched alkyl with 1-6 carbon atoms or alkenyl with 2-6 carbon atoms, a R11and R12the same or different and mean hydrogen, unbranched or branched alkyl with 1-6 carbon atoms or an unbranched or branched acyl with 1 to 8 carbon atoms, unsubstituted or substituted group of the formula-NR13/R14in which R13and R14the same or different and mean hydrogen or an unbranched or branched acyl with 1 to 8 carbon atoms,

R6is hydrogen, a carboxy group, an unbranched or branched alkoxycarbonyl with 1-5 carbon atoms in the CNS part or unbranched or branched alkyl with 1-6 carbon atoms, unsubstituted or substituted by hydroxy group or a group of the formula-O-CO-R15in which R15means phenyl, sesamestreetbeginnin or branched alkyl or alkenyl 1-22 carbon atoms, unsubstituted or substituted group of the formula-OR16in which R16means hydrogen, benzyl, or unbranched or branched acyl with 1 to 6 carbon atoms,

R7hydrogen, or

R6and R7together mean a group of the formula, = O,

the mixture of their isomers and individual isomers and their pharmaceutically acceptable salts.

As pharmaceutically acceptable salts include, for example, salts of the proposed compounds with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred are, for example, salts with hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonate, econsultation, toluensulfonate, benzosulfimide, naphthalenedisulfonate, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Further pharmaceutically acceptable salts are salts of metals of the proposed compounds or their ammonium salts containing a free carboxyl group. Particularly preferred are, for example, sodium, ka is how, for example, ethylamine, diethylamine, triethylamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, Ethylenediamine or 2-phenethylamine.

The proposed connection may exist in stereoisomeric forms, or as image and mirror image (enantiomers) or are not available as image and mirror image (diastereomers). The invention relates to enantiomers and diastereoisomers and their mixtures. Mixtures of enantiomers and diastereomers known method can be divided into pure stereoisomeric components.

Preferred are compounds of General formula (I) in which R1and R2along with connecting them to a double bond means phenyl or peregrinae ring or a ring of the formula

< / BR>
which R8means hydrogen or an unbranched or branched alkyl with 1 to 3 carbon atoms,

R3and R4along with connecting them to a double bond means a phenyl ring or cyclopenten, cyclohexen, cycloheptene, cyclooctene, and specified for R1/R2and R3/R4ring unsubstituted or substituted by 1 or 2 identical or different substituents selected is, razvetvlennye or branched alkoxycarbonyl with 1-4 carbon atoms in the CNS part and unbranched or branched alkyl with 1-4 carbon atoms, unsubstituted or substituted by hydroxy group,

D is hydrogen, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl or unbranched or branched alkyl with 1-10 carbon atoms,

E - group-CO - or-CS-,

L is an oxygen atom, a sulfur, or a group of the formula-NR9in which R9means hydrogen or an unbranched or branched alkyl with 1-5 carbon atoms, unsubstituted or substituted hydroxy group, or phenyl,

R5is phenyl, pyridyl, thienyl, unsubstituted or substituted by 1 or 2 identical or different substituents selected from the group comprising fluorine, chlorine, bromine, unbranched or branched alkoxycarbonyl with 1-4 carbon atoms in the CNS part, unbranched or branched alkyl with 1 to 5 carbon atoms, unsubstituted or substituted by hydroxy group, and/or a group of the formula-OR10or-NR11R12in which R10means hydrogen or an unbranched or branched alkyl with 1-4 carbon atoms or alkenyl with 2-4 carbon atoms, a R11and R12the same or the hydrated or branched acyl with 1 to 6 carbon atoms, unsubstituted or substituted group of the formula-NR13R14in which R13and R14the same or different and mean hydrogen or an unbranched or branched acyl with 1 to 6 carbon atoms,

R6is hydrogen, a carboxy group, an unbranched or branched alkoxycarbonyl with 1-4 carbon atoms in the CNS part or unbranched or branched alkyl with 1-5 carbon atoms, unsubstituted or substituted by hydroxy group or a group of the formula-O-CO-R15in which R15means phenyl, unsubstituted or one - to three-fold substituted unbranched or branched alkyl with 1-4 carbon atoms, or an unbranched or branched alkyl or alkenyl with 2-20 carbon atoms, unsubstituted or substituted group of the formula-OR16in which R16means hydrogen, benzyl, or unbranched or branched acyl with 1 to 5 carbon atoms,

R7hydrogen, or

R6and R7together mean a group of the formula, =O,

the mixture of isomers or individual isomers and their pharmaceutically acceptable salts.

Especially preferred are compounds of General formula (I), in which

R1and R2along with connecting them duojet hydrogen or methyl, R3and R4along with connecting them to a double bond means a phenyl ring or cyclopenten, cyclohexen, cycloheptene, cyclooctene,

moreover, these for R1/R2and R3/R4ring unsubstituted or substituted by 1 or 2 identical or different substituents selected from the group comprising trifluoromethyl, unbranched or branched alkoxy group with 1 to 3 carbon atoms, unbranched or branched alkoxycarbonyl with 1-3 carbon atoms in the CNS part and unbranched or branched alkyl with 1-3 carbon atoms, unsubstituted or substituted by hydroxy group,

D is hydrogen, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or unbranched or branched alkyl with 1-6 carbon atoms,

E - group-CO - or-CS-,

L is an oxygen atom, a sulfur, or a group of the formula-NR9in which R9means hydrogen or an unbranched or branched alkyl with 1 to 4 carbon atoms, unsubstituted or substituted hydroxy group, or phenyl,

R5is phenyl, pyridyl, thienyl, unsubstituted or substituted by 1 or 2 identical or different substituents selected from the group comprising nitro group, carboxy group, fluorine, chlorine, bromine, nerazvit sweetlenny alkyl with 1 to 4 carbon atoms, unsubstituted or substituted by hydroxy group, and/or a group of the formula-OR10or-NR11R12in which R10means hydrogen or an unbranched or branched alkyl with 1-3 carbon atoms or alkenyl with 2-3 carbon atoms, and R11and R12the same or different and mean hydrogen, unbranched or branched alkyl with 1 to 4 carbon atoms or an unbranched or branched acyl with 1 to 5 carbon atoms, unsubstituted or substituted group of the formula-NR13R14in which R13and R14the same or different and mean hydrogen or an unbranched or branched acyl with 1 to 6 carbon atoms,

R6is hydrogen, a carboxy group, an unbranched or branched alkoxycarbonyl with 1 to 3 carbon atoms in the CNS part or unbranched or branched alkyl with 1-4 carbon atoms, unsubstituted or substituted by hydroxy group or a group of the formula-O-CO-R15in which R15means phenyl, unsubstituted or one - or three-fold substituted unbranched or branched alkyl with 1-3 carbon atoms, or an unbranched or branched alkyl with 1 to 19 carbon atoms or alkenyl with 2-19 carbon atoms, nezalezny or branched acyl with 1 to 4 carbon atoms,

R7hydrogen, or

R6and R7together mean a group of the formula, =O,

the mixture of isomers or individual isomers and their pharmaceutically acceptable salts.

The proposed compounds of General formula (I) can be obtained, for example, by transferring the compounds of General formula (II)

< / BR>
in which

R1, R2, R3, R4and D have the above values,

in the amide using compounds of General formula (III)

< / BR>
in which R5have the above values,

R17is specified for R6value, except carboxy group,

in an inert solvent and in the presence of bases and/or auxiliaries,

if necessary with subsequent variation of functional groups by hydrolysis, esterification or recovery.

Receipt of the proposed compounds can be described, for example, using the following scheme I (see the end of the description).

As a solvent in the amidation suitable inert organic solvents which do not change under the reaction conditions. These include ethers, such as, for example, a simple diethyl ether or tetrahydrofuran, halogenated hydrocarbons, ka is len, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile and triamide hexamethylphosphoric acid. In addition, you can use a mixture of these solvents. Especially preferred are dichloromethane, tetrahydrofuran, acetone or dimethylformamide.

As grounds suitable inorganic or organic bases. Preferred are the alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide of the alkaline earth metals, such as barium hydroxide, carbonates of alkali metals such as sodium carbonate or potassium carbonates of alkaline earth metals, such as calcium carbonate or alcoholate of an alkaline or alkaline earth metals, such as methanolic or ethanolic or sodium or potassium tert.butyl potassium, organic amines (trialkylamine with 1 to 6 carbon atoms in each alkyl part, as, for example, triethylamine, or heterocycles as 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-undec-7-ene, pyridine, diaminopyridine, methylpiperidine or morpholine. In addition, as the bases can also use alkaline metals, as, Leah and triethylamine.

The base is used in amounts of 1 to 5 mol, preferably 1 to 3 mol per mol of compound of General formula (II).

The reaction is usually carried out at a temperature from 0 to 150oC, preferably from +20 to +110oC, at atmospheric pressure or at elevated or reduced pressure of, for example, 0.5 to 5 bar. Typically operate at atmospheric pressure.

If necessary, the amidation can be performed more intense by using golodnikov acids, which can be obtained from the corresponding acids by reacting with thionyl chloride, trichloride phosphorus, pentachloride phosphorus, tribromide phosphorus or oxalylamino.

If necessary, these grounds can also be used as acid binding auxiliary substances in the amidation.

As auxiliary agents suitable reagents dehydration. These include, for example, carbodiimide as diisopropylcarbodiimide, DICYCLOHEXYL-carbodiimide or hydrochloride N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, carbonyl compounds, such as, for example, carbonyldiimidazole, 1,2-oxazolium compounds, such as 3-sulfonate 2-ethyl-5-phenyl-1,2 - OK who-(dimethylamino)phosphonium, amide complex diphenyl ether phosphonic acid, the acid chloride of methansulfonate, if necessary in the presence of a base, such as triethylamine, N-ethylmorpholine, N-methylpiperidine or dicyclohexylcarbodiimide and N - oxysuccinimide.

Linking acid agents and agents dehydration is usually used in an amount of from 0.5 to 3 mol, preferably 1 to 1.5 mol per mol of the corresponding carboxylic acid.

The variation of functional groups, for example, by hydrolysis, esterification or recovery and separation of isomers and receiving salts is carried out by known methods.

Carboxylic acids of General formula (II) are new, so they are a further object of the invention. They can be obtained by reacting compounds of General formula (IV)

< / BR>
in which D has the above value,

T - typical tsepliaeva group, such as chlorine, bromine, iodine, tosylate or mesilate, preferably bromine,

R18is alkyl with 1 to 4 carbon atoms, with a compound of General formula (V)

< / BR>
in which R1, R2, R3and R4have the above values,

in an inert solvent, if necessary and, do not change under the reaction conditions. Preferred are ethers, such as, for example, a simple diethyl ether, dioxane, tetrahydrofuran, simple glycolytically ether, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, esters of acetic acid, triethylamine, pyridine, dimethylsulfoxide, dimethylformamide, triamide hexamethylphosphoric acid, acetonitrile, acetone or nitromethane. In addition, you can use a mixture of these solvents. Especially preferred are dimethyl formamide and tetrahydrofuran.

As grounds suitable inorganic or organic bases. Preferred are the alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide of the alkaline earth metals, such as barium hydroxide, carbonates of alkali metals, such as sodium carbonate or potassium carbonates of alkaline earth metals, such as calcium carbonate or alcoholate of an alkaline or alkaline earth metals, such as methanolic or ethanolamines part), as, for example, triethylamine, or heterocycles as 1,4-diazabicyclo[2.2.2] octane, 1,8 - diazabicyclo[5.4.0]-undec-7-ene, pyridine, diaminopyridine, methylpiperidine or morpholine. In addition, as the bases can also use alkaline metals, such as sodium, and their hydrides, such as sodium hydride. Preferred are sodium hydride, potassium carbonate, triethylamine, pyridine, tert. butyl potassium, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,4 - diazabicyclo[2.2.2]octane.

Usually the base is used in amounts of from 0.05 mol to 10 mol, preferably from 1 mol to 2 mol per mol of compound of General formula (IV).

The interaction of compounds of General formula (IV) with a compound of General formula (V) expediently carried out at a temperature from -30 to +100oC, preferably from -10 to +60oC, and typically operate at atmospheric pressure, although it is also possible to work at elevated or reduced pressure of, for example, 0.5 to 5 bar.

Compounds of General formula (III) is known.

Compounds of General formula (VI) and (V) are known or can be obtained analogously to known methods.

The proposed compounds of General formula (I) possess an unexpected range farmakologicheskogo on the walls of blood vessels, and also for the treatment of coronary heart disease, heart failure, impaired brain function, ischemic brain diseases, apoplexy, violations of local blood circulation, disorders of microcirculation and thrombosis. Occlusion of blood vessels plays a crucial role proliferation of smooth muscle cells. The proposed compounds are able to inhibit such proliferation and, thus, atherosclerotic processes. The proposed compounds are characterized by their ability to decrease associated with apolipoprotein B-100 lipoproteins (VLDL and products of its decomposition, for example, low-density lipoprotein), apolipoproteins In-100, triglycerides and cholesterol, that is, they possess valuable pharmacological properties. Unexpectedly, the effect of the proposed compounds is primarily in the reduction or complete inhibition of the formation and/or release associated with apolipoprotein B-100 lipoproteins from liver cells, which leads to lower levels of very low density lipoproteins in the plasma. Such reduction in the level of VLDL necessarily associated with lower levels of apolipoprotein b-100, lipoprotei is the R risk factors contributing to the changes of the vascular wall. Therefore, another object of the invention is a pharmaceutical composition inhibiting the release associated with apolipoprotein B - 100 lipoproteins containing at least one pharmaceutically acceptable carrier and at least one compound of the above General formula (I) in the form of mixtures of isomers or a single isomer, in free form or in pharmaceutically acceptable salt in an effective amount.

Biological activity of compounds of General formula (I) is proved in the following examples.

1. Inhibition of the release associated with apolipoprotein B-100 (Ares-100) lipoprotein

Experience in inhibition of the release associated with Ares-100 lipoproteins from liver cells was performed in vitro using cultured liver cells, preferably human cells line HepG2. These cells are grown under standard conditions in the environment for cultures of eukaryotic cells, preferably in medium RPMI 1640 containing 10% fetal calf serum. Cells HepG2 synthetiseur and isolated in the supernatant liquid particles associated with apolipoprotein B-100 lipoprotein, which in principle is ucture. In the case of human low density lipoprotein presence of these particles can be proved with the help of immunological analysis, which is carried out using antibodies against human low density lipoprotein induced under standard conditions in the rabbit. Antibodies against low density lipoprotein (Kan-anti-LDL-Ak) was purified by affinity chromatography on immunosorbent assay using human low density lipoprotein. Peeled Kan-anti - LDL-Ak adsorb to plastic surfaces. It is advisable their adsorb to plastic surfaces microtitre plates provided with recesses 96, preferably of tiles of type MaxiSorp. If in the supernatant of cells Hep-G2 are associated with apolipoprotein B-100 particles, they can contact Kan - anti/LDL-Ak, and formed immunocomplex associated with the plastic surface. Not related proteins are removed by washing. The presence associated with plastic surface immunocomplex prove using monoclonal antibodies, induced under standard conditions against human low density lipoprotein, followed by purification. These antibodies conjugatively with enzyme percoce the Le acidification of the reaction mixture by adding sulfuric acid to determine the specific light absorption at 450 nm, representing a measure of the amount of associated with apolipoprotein B-100 particles selected HepG2 cells in the supernatant.

Suddenly the proposed compounds inhibit the release associated with apolipoprotein B-100 particles. The value KT50specifies the concentration of the corresponding compound leading to 50% reduction in absorption compared to the control (solvent without active substance).

Connection - KT50< / BR>
example N - [10-9mol/l]

1 - 2,8

5 - 1,1

31 - 170

50 - 29

2. Definition secretion of very low density lipoproteins in vivo in hamster

The proposed compounds on the secretion of very low density lipoproteins in vivo research on hamster. To do this, hamsters after preliminary give atropine (83 mg/kg subcutaneously) narcotized by giving clavata (83 mg/kg subcutaneously) and Nembutal (50 mg/kg intraperitoneally). In the absence of reflexes in animals open them to make available the jugular vein in which to insert the cannula. Then give 0.25 ml/kg of a 20% aqueous solution of Triton WR-1339 in physiological salt solution. This detergent inhibits lipoprotein lipase and thus leads to a higher level is to increase the level of triglycerides can be taken as measures of secretion of VLDL. Before giving detergent and after one hour and two hours after giving blood sample by aspiration retroorbital venous plexus. The blood is incubated for two hours at room temperature and at a temperature of 4oC during the night to complete the coagulation. Then centrifuged for 5 minutes at 10000 g. Using a modified enzyme analysis, which can be purchased in trade (analysis Merckotest Trigly-ceride 14354 N) determine the concentration of triglyceride in the thus obtained serum. For this purpose, 100 μl of serum provided with recesses 96 tiles add 100 µl of the tested compound and incubated at room temperature for 10 minutes. Then automatically the reader (SLT - Spectra) determine the optical density at a wavelength component 492 nm. Serum samples containing triglyceride in too high concentrations, diluted by the addition of physiological saline. The concentration of triglyceride in the sample is determined using measured parallel to the standard curve. The compounds in this experience give or intravenously immediately before the giving of the detergent, or orally, or PADCO the
2 - 10 - 15

5 - 3 - 6

7 - 10 - 20

3. The inhibition of the absorption of triglycerides in the rat intestine in vivo

Connections subject to study on their inhibiting the absorption of triglycerides in vivo actions, give orally to male rats of Wistar breed body weight of 170 - 230, For this 18 hours before giving the corresponding compound of animals are divided into groups of 6 animals, and they have no food but drinking water provide, without limitation. Animals of the control group is given water traganou suspension or traganou suspension containing olive oil. Containing olive oil traganou suspension is obtained using mixer brand Ultra-Turrax. Want to study the connection is suspended directly in front of the cottage in the corresponding containing olive oil truganini suspension, also using a mixer Ultra-Turrax.

Before giving via a stomach tube for determining the content of triglyceride in the basal serum from each rat take blood by puncture of retroorbital venous plexus. Then containing tragant suspension, traganou suspension without compound (control) and connections containing suspended in olive oil truganini suspension VI is of the triglyceride in the serum after a meal hour, two hours and three hours after receiving the connection via a stomach tube.

Blood samples are centrifuged and, after receiving the serum concentration of triglycerides is determined by photometry using the apparatus of EPOS-Analyzer 5060 (firm Eppendorf Geratebau, Netheler &Hinz GmbH/ , Hamburg, DE). Determination of triglycerides is carried out exclusively with the use of enzymes by standard UV analysis.

Data on the increase of triglyceride in serum after a meal is obtained by subtracting the initial amount of the triglyceride of each animal on the concentration of triglycerides after a meal (an hour, two hours and three hours after the issuance of the tested compound).

Get average values of the differences (in mmol/l) animals in each group at each time (hour, two hours, three hours), and the average value increase of the level of triglyceride in serum (TG) treated with investigational compound animals compared with animals given only containing oil traganou suspension.

Determine the content of triglyceride in the serum of animals who gave only tragant. The effect of the compounds in each moment (after one hour, two hours, three casmg tested compound per kg of body weight when giving oral to increase the triglyceride (%) after two hours after loading triglyceride in the serum of rats, not eating. The increase in triglycerides in the serum of control animals, Laden with oil, the level of triglycerides in the serum of control animals, which gave tragant, corresponds to 100%. Each group contained 6 animals.

The increase of triglyceride in serum in % after 2 hours after giving

The amount of triglyceride - 100

Control (tragant) - 0

The studied compound at 10 mg/kg body weight, oral giving

Example 10 - 34

Example 66 - 67

Example 54 - 54

Example 71 - 18

Example 5 - -16

Example 20 - 35

For statistical evaluation using Student's t-test after a preliminary test of homogeneity of the studied compounds.

Compounds that at one point of measurement to reduce the increase of triglyceride in serum after ingestion of at least 30% compared with control (p < 0.05), and seen as having a pharmacological action.

New derivatives of cycloalkane-indole-azaindole General formula (I) can also be used in combination with an inhibitor of glucosidase and/or amylase for family therapy hyperlipidemia, obesity and diabetes. Inhibitors of glucosidase and/or amylase represent noprint AI-3688, trestain, pademelon-Q and talbotton.

Preferred is a combination of acarbose, miglitol, emiglitate or voglibose with one of the above compounds of General formula (I).

New active substances is possible in a known manner to transfer in the usual preparations, such as tablets, coated tablets, capsules, pills, granules, aerosols, syrups, emulsions, suspensions or solutions, using inert, non-toxic, pharmaceutically acceptable carriers or solvents. While having a therapeutic effect of the compounds present in concentrations of about 0.5 to 90% by weight of the total mixture, i.e. in amounts that achieve the indicated doses.

Medications get, for example, by adding solvents and/or carriers for active substances, if necessary with the use of emulsifiers and/or dispersing agents, whereby, for example, in the case of using water as a diluent in case you need to use an organic solvent as an auxiliary solvent.

Drugs are a common method, preferably orally or parenterally, in particular crazyace or intravenously.

In the case of Parente is 2">

In General to achieve the desired effect appropriate was the summer residence of the active substance in an amount of about 0.001 to 1 mg per kg of body weight, preferably about 0.01 to 0.5 mg per kg of body weight, if it is given intravenously, and in an amount of about -20 0,01 mg / kg body weight, preferably 0.1 to 10 mg per kg of body weight in the case of oral testimony.

But may require deviation from these quantities, depending on the body weight or the method for delivering an active substance, the individual response to the active substance, the type of preparation and time or interval villas. Thus, in some cases it may be sufficient to use less than the specified minimum number of the active substance, while in other cases it will be necessary to give more than the specified maximum. In the case of villas active substances in larger quantities it can be recommended giving several separate doses given within one day.

In the following examples for isomers used the following abbreviations:

diaA = diastereoisomer with a higher value of Rf< / BR>
diaB = diastereoisomer with a lower value of Rf< / BR>
ent = enantiomer

R = R-enantiomer

rac = racemate

rac dia A = racemizes is the group of Rf< / BR>
S = S-enantiomer

In addition, still used the following abbreviations:

Ac = acetyl

AcOH = acetic acid

iBu = ISO-butyl

nBu = n-butyl

sBu = -butyl

tBu = tert.butyl

Et = ethyl

cHept = cycloheptyl

cHex = cyclohexyl

Me = methyl

cPent = cyclopentyl

nPent = n-pentyl

Ph = phenyl

iPr = isopropyl

TMS = tetramethylsilane was

EI = e ei

CI = impact ionization

MS = mass spectrum

FAB = fast atom bombardment

Fp= melting point

The tables show the following eluent:

Solvent - Symbol

Dichloromethane and methanol 20:1 - A

Dichloromethane and methanol 50:1 - B

Dichloromethane and ethanol 20:1 - C

Dichloromethane and ethanol 50:1 - D

Petroleum ether and complex ethyl ester acetic acid 1:1 - E

Dichloromethane, methanol and acetic acid 90:10:2 - F

Petroleum ether and complex ethyl ester acetic acid 2:1 - G

Petroleum ether and complex ethyl ester acetic acid 10:1 - H

Toluene - I

Toluene and complex ethyl ester acetic acid 1:1 - K

Petroleum ether and complex ethyl ester acetic acid 5:1 - L

Dichloromethane - M

Petroleum ether and complex ailxeznot acid 1:1 - P

Toluene and complex ethyl ester acetic acid 9:1 - Q

Toluene and complex ethyl ester acetic acid 8:1 - R

Petroleum ether and complex ethyl ester acetic acid 1:2 - S

Dichloromethane and ethanol 5:1 - T

Dichloromethane and ethanol 10:1 - U

Used for thin-layer chromatography eluent VAVA receive the following way:

Mix 87,9 ml water 0,06667-molar solution of potassium phosphate and 12.1 ml of water 0,06667-molar solution of phosphate disodium. 60 ml of the resulting solution is shaken with 200 ml of n-butyl acetate, 36 ml of n-butanol and 100 ml of glacial acetic acid, and the aqueous phase is separated. The organic phase represents the eluent BABE.

The source connection

Example I

1 allyloxy-2-chloromethyl-benzene

< / BR>
To 11,5 g (70 mmol) of 1-allyloxy-2-oxymethyl-Anzola in 110 ml of dichloromethane at a temperature of 0oC add to 11.6 ml (84 mmol) of triethylamine, and then slowly subjected to interaction with a 5.4 ml (70 mmol) of acid chloride of methansulfonate. After 4 hours repeatedly extracted with water, the organic phase is dried over magnesium sulfate and evaporated. The remainder of the solvent is removed in high vacuum.

Yield: 8.5 g

The value of Rf: 0,23 (and (16.4 mmol) obtained according to example I compound in 250 ml of saturated methanolic ammonia solution is refluxed for 17 hours. The reaction mixture is evaporated in vacuum, served in methanol and re-evaporated; data techniques, repeat several times. The crude product is served in dichloromethane and repeatedly extracted with water. The aqueous phase is evaporated almost completely, and get the oil, which solidifies when left to stand. Output: 0,454 g crude product.

The product is used for further reaction without purification.

The value of Rf: 0,41 (eluent: VAVA)

Example III

6-chloro-2,4-lutidine

< / BR>
To obtain the target compounds known from the application of the U.S. N 3632807, 600 r (4,91 mol) of 6-amino-2,4-lutidine dissolved in 2 l of methanol, and the solution at a temperature of about 0oC is saturated with hydrochloric gas. When the temperature of the reaction mixture below 10oC for about 2.5 hours drops add 1,307 l (9,82 mol) of isopentylamine, and the mixture is left to stand when heated to room temperature (approximately 25oC) for 15 hours. The solvent is almost completely removed in vacuum, add 3 l of dichloromethane and 1.5 l of water, and cooled (< 20oC) adding a concentrated aqueous solution of ammonia to bring the pH value, amounting to 9.5. The separated organic phase is dried over sulfate NAT
Boiling point: 47 - 49oC at 12 Torr

Output: 603 g

The second fraction:

Boiling point: 82 - 85oC at 12 Torr

Output: 612 grams (approximately 88% raw)

The value of Rf: 0,39 (from a mixture of petroleum ether and ether complex of acetic acid in the ratio 10:1)

1H-NMR (CDCl3, 200 MHz, TMS): = 2,28 (s, 3H), 2,47 (s, 3H), to 6.88 (s, 1H), of 6.96 (s, 1H).

The crude product, which may contain a small amount of 6-methoxy-2,4-lutidine, used without purification for further reactions.

Example IV

6 hydrazino-2,4-lutidine(4,6-dimethyl-2-hydrazino - pyridine)

< / BR>
580 g (4,10 mol) obtained according to example III compound is dissolved in 800 ml of diethylene glycol, and together with 1050 ml of hydrazine hydrate are stirred at a bath temperature of approximately 140oC, for 48 hours. The cooled reaction mixture is poured on 4.5 l simple ether and 4.5 l of water, and the organic phase is extracted twice, each time using a 2.3 liter dichloromethane. The combined organic phases are dried over sodium sulfate and evaporated in vacuum. Receive 784 g of crude product, still containing solvent, which is used without purification for further reactions.

The value of Rf: about 0,37 (from a mixture of dichloro is H), 6.35mm (s, 1H), 7,11 (s, 1H).

Example V

2 hydrazino-picoline(2-hydrazino-4-methylpyridin)

< / BR>
2 hydrazino-4-picoline is obtained from 2-chloro-4-picoline similarly to the method according to example IV.

The value of Rf: 0,06 (from a mixture of dichloromethane and methanol in the ratio 10:1)

Example VI

2,4-dimethyl-5,6,7,8-tetrahydro -- carboline

< / BR>
78 g (maximum of 0.49 mol) of the crude compound obtained according to example IV at room temperature (approximately 25oC) is subjected to interaction with 59 ml of 0.56 mol) of cyclohexanone, and increases the temperature of the reaction mixture. After 2 hours no longer have the educt (monitoring by thin-layer chromatography using a mixture of dichloromethane and methanol in the ratio 10:1). The reaction mixture is poured into 40 ml of diethylene glycol, and the reaction is carried out at a temperature phlegmy, and by distillation on a water separator to remove components boiling point below the boiling point of the solvent (for example, the reaction water and excess cyclohexanone). After 3 hours no longer have the hydrazone (monitoring by thin-layer chromatography using a mixture of petroleum ether and ether complex of acetic acid in the ratio 1:1). The reaction dare, additionally washed with acetone and dried in vacuum, and obtain 34.4 g of product. Royal solutions, almost solvent free, re-treated with acetone, and get another 9.3 g of product (total yield on three stages: 43,7 g (0.22 mol, 47% of theory).

Melting point: 248oC

The value of Rf: 0,41 (from a mixture of dichloromethane and methanol in a ratio of 20:1)

1H-NMR (d6-DMSO, 200 MHz, TMS): = 1,78 (m, 4H), 2.40 a (s, 3H), 2,48 (s, 3H), of 2.64 (m, 2H), 2,82 (m, 2H), to 6.57 (s, 1H), 10,84 (s, 1H).

In table I the compounds obtained by the method described in example VI.

Example XIX

2,4-dimethyl-carbolin

< / BR>
100 g (499 mmol) obtained according to example VI compounds in 700 ml of diethylene glycol at a temperature of phlegmy and in the presence of 52 g of a 5% palladium on coal is subjected to interaction with 164 ml (1 mol) diethyl ether complex fumaric acid. At high temperature the reaction mixture by distillation separates a small amount of ethanol (if necessary use a separator). After about 8 hours no longer have the educt (monitoring by thin-layer chromatography using a mixture of petroleum ether and ether complex of acetic acid in soothes the hot condition to lighten served through filterpress (firm Seitz) and further washed with hot acetone. Upon cooling, a precipitate, from which the suction, washing with cold acetone and drying in vacuo get a 58.3 g of the product. From the mother liquor acetone is almost completely removed in vacuum and the resulting residue is treated as described above, and receive an additional 9.4 g of product. From the filtrate re-remove the acetone and, after the addition of n-pentane again receive the product as a residue (3.1 g, processing, see above); total yield: 72% of theory.

Melting point: 220 - 221oC

The value of Rand: 0,47 (from a mixture of petroleum ether and ether complex of acetic acid in the ratio 1:1)

1H-NMR (d6-DMSO, 200 MHz, TMS): = 2,54 (s, 3H), of 2.75 (s, 3H), 6.89 in (s, 1H), 7,20 (m, 1H), 7,40 (m, 1H), of 7.48 (DD, 1H), with 8.05 (DD, 1H), of 11.61 (s, 1H).

Example XX

Complex tert.butyl ether 4-were-acetic acid

< / BR>
450 g (3 mol) 4-were-acetic acid (Aldrich company), 1,13 l (12 mol) of tert. butanol and 90 g (of 0.74 mol) of 4-(N,N-dimethylamino) pyridine are dissolved in 2 l of dichloromethane. Add 680 g (3.3 mol) of dicyclohexylcarbodiimide dissolved in 400 ml of dichloromethane, and then stirred at a temperature of 25oC for 20 hours, the precipitated urea is sucked off, washed using 200 ml of dichloromethane, and oranicheskih phase is concentrated and subjected to distillation.

Output: 408 g (66% of theory)

Melting point: 73 - 78oC/0.2 mm

Example XXI

Tert.butyl ether 2-cyclopentyl-2-(4-were)acetic acid

< / BR>
of 33.5 g (0.3 mol) of tert.the butyl potassium at a temperature of 0oC serves in 100 ml of anhydrous dimethylformamide, and add drops of 51.6 g (0.25 mol) of the compound obtained according to example XX, 250 ml of anhydrous dimethylformamide. Stir at a temperature of 0oC for 30 minutes, then at a temperature of 5 - 15oC drops add to 32.2 ml (0.3 mol) of cyclopentylamine in 150 ml of anhydrous dimethylformamide and stirred at a temperature of 25oC for 20 hours. Concentrated, the residue partitioned between water and simple diethyl ether, the ether phase is dried over sodium sulfate and concentrated. The product crystallizes.

Output: 67 g (97.5% of theory)

Melting point: 51 - 53oC

In table II connection receive according to the method similar to example XXI.

Example XXVIII

Complex tert.butyl ether of 2-(4-methyl bromide-phenyl)-2-cyclopentyl - acetic acid

< / BR>
a 27.4 g (0.1 mol) of the compound of example XXI was dissolved in 200 ml of carbon tetrachloride and heated to boiling. Add 0,82 g azobisisobutyronitrile, and then portions we use the temperature 0oC, and succinimide separated by filtration. After concentration of the filtrate, the product falls. It is washed with petroleum ether and dried.

Yield: 20 g (57% of theory)

Melting point: 73 - 76oC

In table III connection receive according to the method similar to example XXVIII.

Example XXXV

Complex tert. butyl ether of 2-(R, S)-2-cyclopentyl-2- [4-(2,3-dimethyl-carbolin-9-yl) methyl] phenylacetic acid

< / BR>
73,6 g (375 mmol) obtained according to example XIX connection in 700 ml of anhydrous N, N-dimethylformamide is subjected to interaction with 42,13 g (375 mmol) of tert.butanolate potassium at a temperature of 25oC for 30 minutes. Then add of 161.7 g (375 mmol) of the compound obtained according to example XXVIII, dissolved in 680 ml of anhydrous N,N-dimethylformamide. The interaction is completed after one hour (monitoring by thin-layer chromatography using a mixture of petroleum ether and ether complex of acetic acid in the ratio 10:1). For processing add 2 l of buffer solution (pH 4, Merck) and 2 l of water, the precipitate is sucked off, washed with water and sucked off again. Slightly wet solid is consistently stirred with petroleum ether theory) of the target product.

Melting point: 160 - 161oC

The value of Rf: 0,39 (from a mixture of petroleum ether and ether complex of acetic acid in the ratio 10:1)

1H-NMR (CDCl3, 250 MHz, TMS): = 0,91 (m, 1H), 1,18 by 1.68 (m, 6H), to 1.87 (m, 1H), 1,47 (s, 9H), 2,42 (m, 1H), 2,66 (s, 3H), and 2.83 (s, 3H), 3,09 (d, 1H), 5,67 (s, 2H), to 6.88 (s, 1H), 7,13 - 7,41 (m, 7H), 8,08 (d, 1H).

Given in tables IV and V connections get method according to example XXXV.

Example LXI

Hydrochloride of 2-(R,S)-2-cyclopentyl-2-[4-(2,4-dimethyl-carbolin-9-yl)- methyl]-phenylacetic acid

< / BR>
139,8 g (298 mmol) of the compound obtained according to example XXXV, dissolved in 1 l of 1,4-dioxane and together with 240 ml of concentrated (37%) hydrochloric acid was stirred at a temperature of 70oC for 3 hours. At the end of the interaction (monitoring by thin-layer chromatography using a mixture of petroleum ether and ether complex of acetic acid in the ratio 10: 1), the reaction mixture is cooled to approximately 15oC, after which portions poured into 5 l of water. The pH was adjusted to 2.8 by addition of 2 M aqueous sodium liquor, the precipitate is sucked off through a paper filter and optionally washed with water until the pH of the wash water does not exceed 4. The solid is sucked off, razmeshivayut phosphorus.

Output: 130,3 g (290 mmol, 97% of theory)

Melting point: 260 - 262oC

The value of Rf: 0,51 (from a mixture of dichloromethane and ethanol in a ratio of 20:1)

1H-NMR (d6-DMSO, 200 MHz, TMS): = 0,88 (m, 1H), 1,09 - to 1.67 (m, 6H), to 1.79 (m, 1H), of 2.38 (m, 1H), 2,68 (s, 3H), 2,84 (s, 3H), and 3.16 (d, 1H), 4,7 - 5,9 (1H), 5,80 (s, 2H), 7,12-7,26 (m, 5H), 7,32 (m, 1H), 7,49 (m, 1H), to 7.59 (d, 1H), 8,17 (d, 1H).

In table VI compounds get method according to example LXI.

Example LXXXI

2-(R,S)-2-[4-(2-methyl-5,6,7,8-tetrahydro -- carboline-9-yl)-methyl-phenyl] -2-cycloheptyl-acetic acid

< / BR>
1.5 g (3,37 mmol) of the compound obtained according to example LIX, within 48 hours subject to interaction with 20 ml of 1 M methanolic sodium lye. Then, water is added, and the methanol evaporated. The alkaline aqueous phase is repeatedly extracted with simple ether residues of the organic solvent is removed in vacuum and at a temperature of 0 to 5oC is brought to a pH value equal to about 2 by adding aqueous 1 M hydrochloric acid. The precipitation is sucked off, washed thoroughly with water and dried in high vacuum over propeciacost phosphorus.

Yield: 1.18 g of the Reaction can be accelerated by using potassium hydroxide instead of sodium hydroxide and adding 1,4,7,10,13,16-hexacosanol acid in the ratio 2:1)

In table VII compounds get method according to example LXXXI.

The compound according to example LXXXII can also be obtained by the following method:

2-[4-(2,4-dimethyl-carbolin-9-yl)-methyl-phenyl] -2-(prop-2-yl)- acetic acid

< / BR>
1,11 g (2.77 mmol) of the compound obtained according to example LV, within 18 hours refluxed together with 45 ml of methanol and 3 ml of 2 M aqueous sodium lye. Because according to the results of thin-layer chromatography (mixture of dichloromethane and methanol in a ratio of 20:1) conversion is incomplete, add 30 ml of tetrahydrofuran and 3 ml of 2 M aqueous sodium liquor, and get a clear solution. Refluxed for 4 hours, after which according to thin-layer chromatography (see above), the interaction is completed. The reaction mixture is cooled, diluted with water and neutralized by addition of 2 M aqueous hydrochloric acid. The precipitate is sucked off, washed with water and dried in vacuum over propeciacost phosphorus.

Output: 0,597 g

Melting point: 225oC

The value of Rf: 0,28 (from a mixture of dichloromethane and methanol in a ratio of 20:1)

In table VIII the connection receiving method according to the example XCI

2 hydrazino-5-triptorelin

< / BR>
2 hydrazino-5-triptorelin get analogously to example IV 2-chloro-5-triptoreline.

The value of Rf: 0,37 (VAVA)

Example XCII

5-oxo-5,6,7,8-tetrahydro -- carboline

< / BR>
3,3 g (19.2 mmol) of 5,6,7,8-tetrahydro -- carboline (see S. Okuda and M. M. Robinson, J. Am. Chem. Soc. 81, page 740, 1959) at a temperature of 0oC while stirring served in 43 ml of tetrahydrofuran, and drops add a solution of 15.5 g (68.2 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 277 ml of tetrahydrofuran and 31 ml of water. The reaction mixture is optionally stirred at a temperature of 0oC for 5 minutes and at a temperature of 20oC for 2 hours, then add a buffer with a pH value equal to 10 (Merck), and extracted with a simple diethyl ether. In the evaporation of the organic phase get the crude product which is purified by chromatography on silica gel 60 (Merck), and as eluent using first a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio of 1: 1, and then a mixture of dichloromethane and methanol in a ratio of 20:1. Thus obtained fraction was stirred with acetone, sucked off, and the solvent is removed in vacuum.

The output is wearing 1:4)

In table X the connection receiving method according to example VI.

In table XI the connection receiving method according to example XIX.

In table XII connections get as in example XXXV.

In table XIII connection get method according to example LXI.

Example XI

1-(R,S)-1-phenyl-2-triphenylmethane-ethanol

< / BR>
13 g (94 mmol) of 1-(R, S)-1-phenyl-2-hydroxy-ethanol at a temperature of 20oC is subjected to interaction with 15.6 ml (113 mmol) of triethylamine and 23.6 g (84,6 mmol) triphenyl-methyl chloride in 200 ml of dimethylformamide. After 20 hours, poured on a buffer having a pH value of 4 (Merck), the phases are separated, the organic phase is dried over magnesium sulfate and evaporated to dryness. The crude product is purified by chromatography on silica gel 60 (Merck) using as eluent a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio of first 20:1 then 10:1.

Output: 27,

The value of Rf: 0,36 (from a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio 5:1)

Example CXII

6-chloro-5-methyl-3-nitro-2-(2-oxo-cyclohexyl)-pyridin

< / BR>
20 g (95,7 melrude 200 ml of dimethylformamide is subjected to interaction with 13.3 ml (or 95.7 mmol) of triethylamine and 14.5 g (95,7 mmol) of freshly distilled 1 - pyrrolidino-cyclopentene. For complete conversion of the starting compounds (monitoring by thin-layer chromatography on silica gel using as eluent a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio 4:1) add 200 ml of 1 M hydrochloric acid, and diluted by adding about 600 ml of water. The precipitation is sucked off, dried in high vacuum over propeciacost phosphorus and purified by chromatography on silica gel 60 (Merck) using as eluent a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio 2:1.

The value of Rf: 0,69 (from a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio 4:1)

Example CXIII

2-methyl-5,6,7,8-tetrahydro -- carboline

< / BR>
2.8 g (10.4 mmol) of the compound obtained according to example CXII, is subjected to a reaction at a hydrogen pressure of 3 bar for 18 hours in an environment of 30 ml of tetrahydrofuran in the presence of 0.5 g of 5% palladium on coal. Then the catalyst is sucked off and washed repeatedly with methanol and dichlormethane. The filtrate is evaporated and dried in high vacuum.

Yield: 2.1 g

The value of Rf: 0,53 (from a mixture of dichloromethane and ethanol in the ratio 5:1)

Example CXIV
oC a precipitate. Add 150 ml of acetone, while stirring cooled to a temperature of 0 to 5oC, the precipitate is sucked off and additionally washed with cold simple ether. The product is dried in high vacuum over propeciacost phosphorus.

Yield: 18 g

The value of Rf: 0,29 (from a mixture of dichloromethane and ethanol in a ratio of 20:1)

Analogously to example XIX receive connections below in table XIV.

Example CXVIII

1-chloro-5,7-dimethyl-carbolin

< / BR>
10.2 g (49 mmol) of the compound obtained according to example CXV, at a temperature of 125oC for 24 hours and subjected to interaction with 222 ml (2.4 mol) of phosphorus oxychloride and 155 μl of N,N-dimethyl-aniline. After ohlazhdeniya and repeatedly extracted with complex ethyl ester of acetic acid. The organic phase is dried over magnesium sulfate, evaporated, and in high vacuum to remove remaining solvent. The crude product is purified by chromatography on silica gel 60 (Merck) using dichloromethane as eluent.

Yield: 4.3 g

The value of Rf: 0,39 (from a mixture of dichloromethane and ethanol in a ratio of 20:1)

Example CXIX

5,7-dimethyl-carbolin

< / BR>
3.8 g (16.5 mmol) of the compound obtained according to example CXVIII, in the presence of 700 mg of 10% palladium on coal at a temperature of 20oC and at a water pressure of approximately 3 bar for 10 days in an environment of 40 ml of tetrahydrofuran is subjected to interaction with 1.3 g of sodium bicarbonate, and a day later add 300 mg of 10% palladium on coal and 5 ml of methanol. Then the catalyst is sucked off through kieselguhr, optionally washed with tetrahydrofuran, boil in the medium of methanol and dichloromethane and again sucked off. The combined organic phases are evaporated, the residue is stirred with simple ether and sucked off. The result of drying in vacuum get 3 g of crude product.

The value of Rf: 0,13 (from a mixture of dichloromethane and ethanol in a ratio of 20:1)

Example XX

5,6-dimethyl-1-(pyrid-2-yl)-1H-benzotriazol

< / BR>
14,85 g (103 mmol) of 5,6-di the interaction with 5 g (104 mmol) 50 7% sodium hydride, containing 40% paraffin oil, until the cessation of hydrogen evolution. Then add 10 g (103 mmol) of 2-fluoro-Piri - DIN and refluxed for 18 hours. After cooling to a temperature of 20oC add water to a volume of about 1 l, the formed precipitate is sucked off and washed with water. The product is dried in high vacuum over propeciacost phosphorus and purified by chromatography on silica gel 60 (Merck) using as eluent a gradient of dichloromethane to a mixture of dichloromethane and ethanol in a ratio of 100:1.

Yield: 10.6 g

The value of Rf: 0,38 (from a mixture of dichloromethane and ethanol in the ratio of 50:1)

Example CXXI

6,7-dimethyl-carbolin

< / BR>
8,9 g (39,7 mmol) of the compound obtained according to example XX, 140 g of polyphosphoric acid in an argon atmosphere slowly heated to a temperature of 165oC, and before complete conversion of the starting compound (monitoring by thin-layer chromatography using a mixture of dichloromethane and ethanol in a ratio of 20:1) was poured onto 1.5 l of water and adjusted to pH 6-7 by addition of 1 M aqueous sodium lye. The formed precipitate is sucked off, washed with water, again sucked off, washed with petroleum ether and MESI dichloromethane and ethanol in a ratio of 20:1)

Similar to the method of example XXI receive are shown in table XV connection.

In table XVI connection receive according to the method in example XXVIII.

The connection is shown as table XVII, get analogously to example XXXV.

In table XVIII connection receive according to the methods described in the examples LXI, LXXXI, LXXXII (second method) or 73.

Receiving target compounds

Examples 1, 2 and 3

N-[(R)-phenylglycinol] 2-(S)- 2-(R)- 2-[4-(2,4-dimethyl-5,6,7,8-tetrahydro - carbolin-9-yl)- methyl-phenyl]-2-cyclopentyl-acetic acid

< / BR>
3.00 g (7.2 mmol) of the compound obtained according to example LXII, and 0.99 g (7.2 mmol) of (R)-phenylglycinol (company Aldrich) dissolved in 70 ml of dichloromethane, at a temperature of 0oC successively added 1.07 g (7.9 mmol) of 1-hydroxy-1H - benzotriazole in the form of a hydrate (Aldrich company), 1,58 g (8.3 mmol) of the hydrochloride of N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide (company Aldrich) and 2 ml of triethylamine, and then further stirred at room temperature for 20 hours. The organic solution is extracted with an aqueous solution of ammonium chloride, aqueous sodium bicarbonate solution and a buffer with a pH value of 4 (prepared buffer solution firm E. Merck in Darmstadt, DE), dried on"ptx2">

The mixture is separated by chromatography on silica gel using as eluent a mixture of dichloromethane and ethanol in the ratio of 50:1, and get:

Example 2:

the diastereoisomer A [2(S)-diastereoisomer]: 1,23 g

The value of Rf: 0,23 (from a mixture of dichloromethane and ethanol in the ratio of 50:1)

1H-NMR (d-DMSO, 250 MHz, TMS): = 0.87 (m, 1H), 1,19 - to 1.63 (m, 6H), 1,72 (m, 1H), 2,45 (m, 1H), 2,58 (s, 3H), and 2.79 (s, 3H), 3,26 (d, 1H), 3,44 - of 3.53 (m, 2H), 4,21 - or 4.31 (m, 2H), 5,63 (s, 2H), 6,97 - 7,11 (m, 8H), 7,20 - 7,28 (m, 3H), 7,41 (m, 1H), 7,54 (d, 1H), 8,12 (d, 1H), 8,24 (d, 1H).

Example 3:

the diastereoisomer B [2(R)-diastereoisomer]: 1.12 g

The value of Rf: 0,16 (from a mixture of dichloromethane and ethanol in the ratio of 50:1)

1H-NMR (d-DMSO, 250 MHz, TMS): = 0,84 (m, 1H), 1,07 - to 1.59 (m, 7H), was 2.34 (m, 1H), 2,61 (c, 3H), 2,80 (c, 3H), of 3.25 (d, 1H), 3.43 points (m, 2H), 4.63 to - 4,72 (m, 2H), to 5.66 (s, 2H), 6,98 (c, 1H), 7,13 (m, 2H), 7,20 - 7,30 (m, 8H), the 7.43 (m, 1H), EUR 7.57 (d, 1H), 8,12 (d, 1H), at 8.36 (d, 1H).

Analogously to examples 1, 2 and 3 receive the compounds listed in tables 1, 2 and 3.

Example 69

N-(2-oxybenzyl)amide and 2-(R, S)-2-[4-(2,4-dimethyl - 5,6,7,8-tetrahydro -- carboline-9-yl)-methyl-phenyl]-2-cycloheptyl - acetic acid

< / BR>
of 0.60 g of the compound obtained according to example 58, refluxed for 22 hours in 3 ml of methanol and 0.6 ml of water in an argon atmosphere as samanata. In the case of incomplete conversion (monitoring by thin-layer chromatography using a mixture of dichloromethane and ethanol in the ratio of 50:1) add 33 g of 10% palladium on animal coal and 33 mg of para-toluenesulfonic acid in the form of a monohydrate and refluxed for further 24 hours. The catalyst sucked off while hot, washed with a large amount of hot methanol, and the filtrate evaporated. The result of drying in high vacuum over propeciacost phosphorus obtain 0.52 g of product.

The value of Rf: 0,33 (from a mixture of dichloromethane and ethanol in the ratio of 50:1)

Example 70

N-(R)-phenylglycinol 2-(R, S)-2-[4-(3-oxymethyl -- carbolin-9-yl)-methyl-phenyl]-2-cyclo-pentyl-acetic acid

< / BR>
To 500 mg (0,868 mmol) of the compound obtained according to example 31, in 5 ml of anhydrous tetrahydrofuran in an argon atmosphere at a temperature of 0oC drops add 1,737 ml (1,737 mmol) of 1 M solution alanate lithium in tetrahydrofuran, and optionally stirred at a temperature of 20oC for 4 hours. To the reaction mixture carefully add 5 ml of water, and by adding a 2 M aqueous hydrochloric acid adjusted to a pH value approximately equal to 2. The aqueous phase is repeatedly extracted with promatory on silica gel 60 (Merck) using as eluent a gradient of dichloromethane to a mixture of dichloromethane and methanol in the ratio of 50:1.

Yield: 0.12 g

The value of Rf: 0,26 (from a mixture of dichloromethane and ethanol in a ratio of 20:1)

Table 4 provides the connection receive according to the method in example 70.

Example 73

N-(4-carboxybenzoyl)amide and 2-(R, S)-2-[4-(2,4-dimethyl-5,6,7,8 - tetrahydro - carbolin-9-yl)-methyl-phenyl]-2 - cycloheptyl-acetic acid

< / BR>
0,325 g (0.55 mmol) of the compound obtained according to example 60, at a temperature of 60oC for 18 hours and subjected to interaction with 0.5 ml of aqueous 2 M sodium liquor in 3 ml of methanol. If according to the control by thin-layer analysis (solvent F) the interaction is not complete, add another 0.5 ml of aqueous 2 M sodium lye in 1 ml of methanol and refluxed for 24 hours. The reaction mixture was cooled by adding 1 M hydrochloric acid adjusted to a pH of about 4. The precipitate is sucked off, washed with water and with a mixture of petroleum ether and simple diethyl ether in the ratio of 5:1, and the remaining solvent removed under high vacuum over propeciacost phosphorus.

Output: 0,154 g

The value of Rf: 0,50 (from a mixture of dichloromethane, methanol and acetic acid in the ratio to 90:10:2)

Example 74

N-(3-carboxyla the x2">

< / BR>
The target connection receive analogously to example 73 from the compound obtained according to example 59.

The value of Rf: 0,27 (from a mixture of dichloromethane and ethanol in a ratio of 20:1)

The compounds listed in tables 5, 6, 7, 8, 9 and 10, get analogously to example 1.

The compounds listed in table II, get similarly to examples 1, 2 and 3.

Compounds shown in table 12, is also obtained according to examples 1, 2 and 3.

Compounds shown in table 13, get analogously to example 73.

Compounds shown in table 14, get analogously to example 70.

Example 138

N-[1-(R, S)-1-(4-acetamido-phenyl)-2-hydroxy - ethyl]amide of 2-(R,S)-2-[4-(2,4-dimethyl - carbolin-9-yl)-methyl - phenyl]-2-cyclopentyl-acetic acid

< / BR>
Part a

To 0,60 g (1.10 mmol) of the compound obtained according to example 137, in 10 ml of dichloromethane add 192 μl (3,29 mmol) of triethylamine, and then at a temperature of 0oC is subjected to interaction with 70 μl (0,99 mmol) acetylchloride. Stir for 3 hours, and the temperature of the reaction mixture increased to 20oC. Then shaken with 1 M hydrochloric acid, 0.1 M sodium lye and water, the organic phase is dried on the C - spectrum (FAB) double acetiminophen (631,57%, M++ H / 653,6%, M++ Na). So it is at a temperature of 20oC for one hour is subjected to interaction in 6 ml of methanol with 2 M sodium lye. The addition of 1 M hydrochloric acid, the pH adjusted to 2, and the resulting reaction mixture is extracted with ether complex of acetic acid. The organic phase is washed with water to neutrality, dried over magnesium sulfate and evaporated in vacuum. The result of drying in high vacuum to obtain 0.28 g of product.

The value of Rf: 0,17 (from a mixture of dichloromethane and ethanol in a ratio of 20:1)

Example 139

N-[1-(R, S)-1-(4-acetamido-phenyl)-2-acetoxy - ethyl] amide of 2-(R,S)-2-[4-(2,4-dimethyl - carbolin-9-yl)- methyl-phenyl]-2-cyclopentyl-acetic acid

< / BR>
The target compound is obtained by interaction of the compound obtained according to example 137, similar to part a of example 138 4 equivalents of triethylamine and 4 equivalents of acetylchloride.

The value of Rf: 0,56 (from a mixture of dichloromethane and ethanol in a ratio of 20:1)

The compounds listed in table 15, get analogously to example 138.

Example 142

N-[1-(R)-1-phenyl-2-acetoxy-ethyl] amide of 2(S)-2- [4-(2,4-dimethyl -- carbolin-9-yl)-methyl-phenyl]-2-cyclopentyl - acetic acid

< / BR>
4.5 g (8,468 mmol) soede,82 ml (25,4 mmol) acetylchloride in 30 ml of dichloromethane and subjected to interaction at a temperature of 20oC for 20 hours. The reaction mixture is extracted with a buffer having a pH value of 2 (Merck) and water, dried over sodium sulfate and evaporated. Then stirred with methanol and dried in high vacuum over propeciacost phosphorus, resulting in a gain of 3.6 g of the product.

The value of Rf: 0,62 (from a mixture of petroleum ether and ether complex of acetic acid in the ratio 1:1)

The compounds listed in table 16, get analogously to example 142.

Example 151

N-[1-(R)-1-phenyl-2-acetoxy-ethyl]amide of 2(S)-2- [4-(2,4-dimethyl -- carbolin-9-yl)-methyl-phenyl]-2-cyclopentyl - teoksessa acid

< / BR>
To 1.5 g (2.6 mmol) of the compound obtained according to example 142, in 50 ml of dioxane is added 1.27 g (3,13 mmol) of 2,4-bis-(4 - methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide, and refluxed for 5 hours. The reaction mixture was vacuum evaporated to dryness and purified by chromatography on silica gel brand MATREX Silica Si (Amicon company, Grace Company, a particle size of 20 μm, a column for high performance liquid chromatography) using as eluent a mixture of dichloromethane and ethanol in a ratio of 100:1.

Output: 665 mg

The value of Rf: 0,53 (from a mixture of petroleum ether and the complex is M+- AcOH).

Example 152

N-[1-(R)-1-phenyl-2-[(2-hydroxy-atet)-oxy] - ethyl]amide of 2(S)-2-[4-(2,4-dimethyl - carbolin-9-yl)-methyl-phenyl]-2 - cyclopentyl-acetic acid

< / BR>
1.45 g (2,13 mmol) of the compound obtained according to example 145, 100 ml of tetrahydrofuran and in the presence of 5% palladium on animal coal is subjected to hydrogenation at a temperature of 20oC and normal hydrogen pressure. After 18 hours the reaction mixture is sucked off through kieselguhr, washed repeatedly with methanol and dichloromethane, and the combined organic solutions evaporated. The solid residue is mixed with pentane, sucked off, and the remaining solvent removed under high vacuum.

The value of Rf: 0,31 (from a mixture of petroleum ether and ether complex of acetic acid in the ratio 1:1)

Example 153

N-[1-(R)-1-phenyl-2-hydroxy-ethyl] -amide 2-(S)-2-[4- (2,4-dimethyl -- carbolin-9-yl)-methyl-phenyl]-2-cyclopentyl - teoksessa acid

< / BR>
The target connection receive at a temperature of 20oC analogously to example 73 from the compound obtained according to example 151, environment dimethoxyethane as solvent.

The value of Rf: 0,24 (from a mixture of dichloromethane and ethanol in the ratio of 50:1)

Example 154

N-[1-(Tien-2-yl)-1->/BR>The target connection receive similarly to examples 1, 2 and 3 from the compound obtained according to example LXII, and complex (R,S)- (Tien-2-yl)-licensedialog ether.

The value of Rf: 0,67 (from a mixture of dichloromethane and ethanol in a ratio of 20:1)

Example 155

N-[1-(Tien-2-yl)-2-hydroxy-ethyl]-amide 2-[4-(2,4 - dimethyl-carbolin-9-yl)-methyl-phenyl]-2-cyclopentyl-acetic acid

< / BR>
The target connection receive analogously to example 70 from the compound obtained according to example 154.

The value of Rf: 0,21 (from a mixture of dichloromethane and ethanol in the ratio of 50:1)

Example 156

N-[1-(R)-1-phenyl-2-(2,4,6-trimethyl-benzoyl-oxy) ethyl] -amide 2-(S)-2-[4-(2,4-dimethyl -- carbolin-9-yl)-methyl - phenyl] -2-cyclopentyl-acetic acid

< / BR>
The target connection receive analogously to example 142 from the compound obtained according to example 2.

The value of Rf: 0,26 (eluent D)

Example 157

Complex (R,S)-1-phenyl-2-triphenylmethane - ethyl ester 2-(R,S)-2-[4-(2,4-dimethyl -- carbolin-9-yl)- methyl-phenyl]-2-cyclopentyl-acetic acid

< / BR>
1.0 g (2,42 mmol) of the compound obtained according to example LXI, in 30 ml of dimethylformamide at a temperature of -30oC for 2 hours and subjected to interaction with 1 ml (7,27 mmol) triethylsilane example CXI, and 296 mg (2,42 mmol) dimethylaminopyridine in 10 ml of dimethylformamide, and additionally stirred for about 20 minutes on a slow heat until the 20oC. processing the reaction mixture while stirring served in a simple mixture of ether and water, the phases are separated, the organic phase is washed with water, 1 M sodium liquor and optionally washed with water. Then the organic phase is dried over magnesium sulfate and evaporated at the end in a high vacuum.

Yield: 1.0 g

The value of Rf: 0,44 (from a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio 5:1)

Examples 158 and 159

Complex 1-(R, S)-1-phenyl-2-triphenylmethane-ethyl ester 2-(R,S)-2-[4-(2,4-dimethyl -- carbolin-9-yl)-methyl-phenyl] -2-cyclopentyl-acetic acid

< / BR>
1.0 g (1,29 mmol) of the compound obtained according to example 157, stirred in 10 ml of tetrahydrofuran and 5 ml of water with 5 ml triperoxonane acid at a temperature of 20oC for 48 hours. Then the reaction mixture is stirred with 300 ml of simple ether and 200 ml of an aqueous solution of sodium bicarbonate, after the cessation of carbon dioxide the phases are separated, and the organic phase is extracted with a buffer with a pH value of 7 (Merck) and dried over sulfate m is measures by chromatography on silica gel (Merck) using as eluent a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio of 5:1.

the racemic diastereoisomer A):

Yield: 300 mg

The value of Rf: 0,54 (from a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio 2:1)

the racemic diastereoisomer):

Yield: 320 mg

The value of Rf: 0,42 (from a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio 2:1)

The compounds listed in table 17, to receive according to the method described in examples 1, 2 and 3.

Example 185

[N-benzyl-N-benzoyl] -amide 2-(R, S)-2-[4-(2,4-dimethyl -- carbolin-9-yl)-methyl-phenyl]-2-cyclopentyl-acetic acid

< / BR>
2.0 g (4.8 mmol) of the compound obtained according to example LXI, in anhydrous dimethylformamide at a temperature of -30oC for one hour is subjected to interaction from 0.74 ml (5.3 mmol) of triethylamine and 0.41 ml (5.3 mmol) of methylchloride. Then at a temperature of -30oC drops add a solution of 1.07 g (5.1 mmol) of N - benzyl-benzamide and of 1.42 ml (10.2 mmol) of triethylamine in 10 ml of anhydrous dimethylformamide, and at slow heating up to 20oC additionally stirred for 16 hours. The reaction mixture is stirred with a simple ether and water, the phases are separated, and the aqueous phase is optionally washed after adjusting to pH 4 7 respectively. Merge is receiving as a first eluent mixture of dichloromethane and ethanol in the ratio of 60:1, and then a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio of 4:1.

The value of Rf: 0,58 (from a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio 2:1)

Example 186

[N-benzoyl] -amide 2-(R,S)-2-[4-(2,4-dimethyl -- carbolin-9-yl)- methyl-phenyl]-2-cyclopentyl-acetic acid

< / BR>
2,0 r (3.3 mmol) of the compound obtained according to example 185, put together in dioxane in the presence of 2 g of 5% palladium on animal coal at a temperature of 20oC and a hydrogen pressure of about 1 bar. Then sucked through the filter type Seitz, optionally washed with dioxane, and the filtrate evaporated. The crude product is at a temperature of 60oC stirred with methanol, sucked off at a temperature of 20oC, washed with cold methanol and dried in vacuum over propeciacost phosphorus.

The value of Rf: 0,49 (from a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio 2:1)

Example 187

N-[1-(R, S)-1-phenyl-1-ethoxy-1-etoxycarbonyl - methyl] -amide 2-(R,S)-2-[4-(2,4-dimethyl -- carbolin - 9-yl)-methyl-phenyl] -2-cyclopentyl-acetic acid

< / BR>
The target connection receive according to examples 1, 2 and 3 from the compound obtained is in-9-yl)-methyl-phenyl]-2 - cyclopentyl-acetic acid

< / BR>
The target connection receive according to example 73 from the compound obtained according to example 187.

Example 189

Complex 1-(R,S)-2-hydroxy-1-phenyl-ethyl ester 2-(R,S)-2-[4-(2,4-dimethyl - carbolin-9-yl)-methyl-phenyl]-2 - cyclopentyl-teoksessa acid

< / BR>
1 g (2,42 mmol) of the compound obtained according to example LXI, in 30 ml of dimethylformamide at a temperature of -30oC for one hour is subjected to interaction with 1 ml (7,27 mmol) of triethylamine and 206 μl (or 2.67 mmol) methylchloride. Then at the same temperature drops, add a solution of 1-(R,S)-1-phenyl-2-hydroxy-diethanol in 10 ml of dimethylformamide and additionally stirred for one hour. For processing the reaction mixture while stirring served in a simple ether and aqueous sodium bicarbonate solution. The organic phase is optionally washed first buffer with a pH value of 2, and then a buffer with pH 7, dried over magnesium sulfate and evaporated. The crude product is purified by chromatography on silica gel 60 (Merck) using as eluent a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio of 5:1.

Output: 660 mg

The value of Rf: 0,58 (from a mixture of petroleum ether and complex ethyl ester acetic ASS="ptx2">

Example 190

Tablets composition: 20 mg of the compound of example 5 as the active substance, 60 mg microcrystalline cellulose (trade product Avicel PH 101), 38 mg of polyvinylpyrrolidone under the trade name Polyplasdone XL 20 mg of polyvinylpyrrolidine a molar mass of 250, 1 mg of sodium dodecyl sulfate and 1 mg of magnesium stearate are prepared as follows.

The compound of example 5 was dispersed in a liquid medium containing polyvinylpyrrolidone with a molecular weight of 250 and sodium dodecyl sulphate. To the resulting dispersion type microcrystalline cellulose and polyvinylpyrrolidon called Polyplasdone X, and the resulting mixture granularit fluidized bed, followed by drying. The resulting granules were sieved, and then add the magnesium stearate. The resulting mixture is stirred and processed into round tablets with a weight of 120 mg and a diameter of 7 mm

Example 191

The compound of example 5 micronizer. Before use, it is suspended in water.

Example 192

Liquid drug composition: 0.1 mg/ml (liquid preparation) compound of example 5 as the active substance, 10% ethanol, 5% of ethoxylated Nonylphenol (trade product Cremophor EL) and water to 100% prepared as follows.

1. Derivatives cycloalkane-indole and azaindole General formula (I)

< / BR>
in which R1and R2along with connecting them to a double bond means phenyl or peregrinae ring or a ring of the formula

< / BR>
in which R8is hydrogen or an unbranched or branched alkyl with 1 to 4 carbon atoms;

R3and R4along with connecting them to a double bond means a phenyl ring or a four-, eight-membered cycloalkanones the rest,

moreover, these for R1/R2and R3/R4ring unsubstituted or substituted by 1 to 3 identical or different substituents selected from the group comprising trifluoromethyl, unbranched or branched alkoxygroup with 1 to 6 carbon atoms, unbranched or branched alkoxycarbonyl with 1 to 6 carbon atoms in the CNS part, unbranched or branched alkyl with 1 to 6 carbon atoms, unsubstituted or substituted by a hydroxy-group;

D is hydrogen, cycloalkyl with 4 to 12 carbon atoms or an unbranched or branched alkyl with 1 to 12 carbon atoms;

E - group-CO - or-CS-,

L - atom oxygen, sulfur or the group-NR9in which R9- in what syruppy or phenyl;

R5is phenyl, pyridyl, thienyl, unsubstituted or substituted by 1 to 3 identical or different substituents selected from the group comprising nitro-group, carboxypropyl, halogen, unbranched or branched alkoxycarbonyl with 1 to 6 carbon atoms in the CNS part, unbranched or branched alkyl with 1 to 6 carbon atoms, unsubstituted or substituted by a hydroxy-group, and/or a group of the formula-OR10or-NR11R12in which R10is hydrogen or an unbranched or branched alkyl with 1 to 6 carbon atoms or alkenyl with 2 to 6 carbon atoms, and R11and R12the same or different, is hydrogen, unbranched or branched alkyl with 1 to 6 carbon atoms or an unbranched or branched acyl with 1 to 8 carbon atoms, unsubstituted or substituted group of the formula-NR13R14in which R13and R14the same or different, is hydrogen or an unbranched or branched acyl with 1 to 8 carbon atoms;

R6- hydrogen, carboxypropyl, unbranched or branched alkoxycarbonyl with 1 to 5 carbon atoms in the CNS part or unbranched or branched alkyl with 1 to 6 carbon atoms, unsubstituted or substituted Ginny unbranched or branched alkyl with 1 to 5 carbon atoms, or an unbranched or branched alkyl with 1 to 22 carbon atoms or alkenyl with 2 to 22 carbon atoms, unsubstituted or substituted group of the formula-OR16in which R16is hydrogen, benzyl or an unbranched or branched acyl with 1 to 6 carbon atoms;

R7is hydrogen or

R6and R7together mean a group of the formula, =O,

the mixture of their isomers and individual isomers and their pharmaceutically acceptable salts.

2. Derivatives cycloalkane-indole-azaindole General formula (I) under item 1, in which R1and R2along with connecting them to a double bond means phenyl or peregrinae ring or a ring of the formula

< / BR>
in which R8is hydrogen or an unbranched or branched alkyl with 1 to 3 carbon atoms;

R3and R4along with connecting them to a double bond means a phenyl ring or cyclopenten, cyclohexen, cycloheptene, cyclooctene, and specified for R1/R2and R3/R4ring unsubstituted or substituted by 1 or 2 identical or different substituents selected from the group comprising trifluoromethyl, unbranched or branched alkoxygroup with 1 to 4 carbon atoms, unbranched by alkyl with 1 to 4 carbon atoms, unsubstituted or substituted by a hydroxy-group, D is hydrogen, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or unbranched or branched alkyl with 1 to 10 carbon atoms, E is a group-CO - or-CS-, L - atom oxygen, sulfur or a group of the formula-NR9in which R9is hydrogen or an unbranched or branched alkyl with 1 to 5 carbon atoms, unsubstituted or substituted by a hydroxy-group or phenyl, R5is phenyl, pyridyl, thienyl, unsubstituted or substituted by 1 or 2 identical or different substituents selected from the group comprising fluorine, chlorine, bromine, unbranched or branched alkoxycarbonyl with 1 to 4 carbon atoms in the CNS part, unbranched or branched alkyl with 1 to 5 carbon atoms, unsubstituted or substituted by a hydroxy-group, and/or a group of the formula-OR10or-NR11R12in which R10is hydrogen or an unbranched or branched alkyl of 1 to 4 carbon atoms or alkenyl with 2 to 4 carbon atoms, and R11and R12the same or different, is hydrogen, unbranched or branched alkyl with 1 to 5 carbon atoms or an unbranched or branched acyl with 1 to 6 carbon atoms, unsubstituted or samisen razvetvlennye or branched acyl with 1 to 6 carbon atoms, R6- hydrogen, carboxypropyl, unbranched or branched

alkoxycarbonyl with 1 to 4 carbon atoms in the CNS part or unbranched or branched alkyl with 1 to 5 carbon atoms, unsubstituted or substituted by a hydroxy-group or a group of the formula-O-CO-R15in which R15is phenyl, unsubstituted or one - trehzameshchenny unbranched or branched alkyl with 1 to 4 carbon atoms, or an unbranched or branched alkyl with 1 to 20 carbon atoms or alkenyl with 2 to 20 carbon atoms, unsubstituted or substituted group of the formula-OR16in which R16is hydrogen, benzyl, or unbranched or branched acyl with 1 to 5 carbon atoms, R7is hydrogen or R6and R7together mean a group of the formula, =O, mixture of isomers, or individual isomers and their pharmaceutically acceptable salts.

3. Derivatives cycloalkane-indole-azaindole General formula (I) under item 1, in which R1and R2along with connecting them to a double bond means phenyl or peregrinae ring or a ring of the formula

< / BR>
in which R8is hydrogen or methyl,

R3and R4along with connecting them to a double bond means phenyl is>R4ring unsubstituted or substituted by 1 or 2 identical or different substituents selected from the group comprising trifluoromethyl, unbranched or branched alkoxygroup with 1 to 3 carbon atoms, unbranched or branched alkoxycarbonyl with 1 to 3 carbon atoms in the CNS part and unbranched or branched alkyl with 1 to 3 carbon atoms, unsubstituted or substituted by a hydroxy-group, D is hydrogen, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or unbranched or branched alkyl with 1 to 6 carbon atoms, E is a group-CO - or-CS-, L -, an oxygen atom, sulfur or a group of the formula-NR9in which R9is hydrogen or an unbranched or branched alkyl with 1 to 4 carbon atoms, unsubstituted or substituted by a hydroxy-group or phenyl, R5is phenyl, pyridyl, thienyl, unsubstituted or substituted by 1 or 2 identical or different substituents selected from the group comprising nitro-group, carboxypropyl, fluorine, chlorine, bromine, unbranched or branched alkoxycarbonyl with 1 to 3 carbon atoms in the CNS part, unbranched or branched alkyl with 1 to 4 carbon atoms, unsubstituted or substituted by a hydroxy-group, and/or a group of the formula-OR1011and R12the same or different, is hydrogen, unbranched or branched alkyl with 1 to 4 carbon atoms or an unbranched or branched acyl with 1 to 5 carbon atoms, unsubstituted or substituted

a group of the formula-NR13R14in which R13and R14the same or different, is hydrogen or an unbranched or branched acyl with 1 to 6 carbon atoms, R6- hydrogen, carboxypropyl, unbranched or branched alkoxycarbonyl with 1 to 3 carbon atoms in the CNS part or unbranched or branched alkyl with 1 to 4 carbon atoms, unsubstituted or substituted by a hydroxy-group or a group of the formula-O-CO-R15in which R15is phenyl, unsubstituted or one - or three-fold substituted unbranched or branched alkyl with 1 to 3 carbon atoms, or an unbranched or branched alkyl with 1 to 19 carbon atoms or alkenyl with 2 to 19 carbon atoms, unsubstituted or substituted group of the formula-OR16in which R16is hydrogen, benzyl, or unbranched or branched acyl with 1 to 4 carbon atoms, R7is hydrogen or R6and R7together mean a group of the formula, =O, mixture of isomers or individual who (II)

< / BR>
in which R1and R2along with connecting them to a double bond means phenyl or peregrinae ring or a ring of the formula

< / BR>
in which R8is hydrogen or an unbranched or branched alkyl with 1 to 4 carbon atoms,

R3and R4along with connecting them to a double bond means a phenyl ring or a four-, eight-membered cycloalkenyl balance, and specified for R1/R2and R3/R4ring unsubstituted or substituted by 1 to 3 identical or different substituents selected from the group comprising trifluoromethyl, unbranched or branched alkoxygroup with 1 to 6 carbon atoms, unbranched or branched alkoxycarbonyl with 1 to 6 carbon atoms in the CNS part, unbranched or branched alkyl with 1 to 6 carbon atoms, unsubstituted or substituted by a hydroxy-group, D is hydrogen, cycloalkyl with 4 to 12 carbon atoms or an unbranched or branched alkyl with 1 to 12 carbon atoms, as starting compounds for obtaining derivatives of cycloalkanones and azaindole General formula (I) on PP.1 - 3.

5. The pharmaceutical composition inhibiting the release associated with apolipoprotein B-100 on the basis of the derived cycloalkane-indole and azaindole, characterized in that, as derived cycloalkane-indole and azaindole it contains a compound of General formula (I)

< / BR>
in which R1and R2along with connecting them to a double bond means phenyl or peregrinae ring or a ring of the formula

< / BR>
in which R8is hydrogen or an unbranched or branched alkyl with 1 to 4 carbon atoms,

R3and R4along with connecting them to a double bond means a phenyl ring or a four-, eight-membered cycloalkenyl balance, and specified for R1/R2and R3/R4ring unsubstituted or substituted by 1 to 3 identical or different substituents selected from the group comprising trifluoromethyl, unbranched or branched alkoxygroup with 1 to 6 carbon atoms, unbranched or branched alkoxycarbonyl with 1 to 6 carbon atoms in the CNS part, unbranched or branched alkyl with 1 to 6 carbon atoms, unsubstituted or substituted by a hydroxy-group, D is hydrogen, cycloalkyl with 4 to 12 carbon atoms or an unbranched or branched alkyl with 1 to 12 carbon atoms, E is a group-CO - or-CS-, L -, an oxygen atom, sulphur or the group-NR9in which R9is hydrogen or neravetla the R5is phenyl, pyridyl, thienyl, unsubstituted or substituted by 1 to 3 identical or different substituents selected from the group comprising nitro-group, carboxypropyl, halogen, unbranched or branched alkoxycarbonyl with 1 to 6 carbon atoms in the CNS part, unbranched or branched alkyl with 1 to 6 carbon atoms, unsubstituted or substituted by a hydroxy-group, and/or a group of the formula-OR10or-NR11R12in which R10is hydrogen or an unbranched or branched alkyl with 1 to 6 carbon atoms or alkenyl with 2 to 6 carbon atoms, and R11and R12the same or different, is hydrogen, unbranched or branched alkyl with 1 to 6 carbon atoms or an unbranched or branched acyl with 1 to 8 carbon atoms, unsubstituted or substituted group of the formula-NR13R14in which R13and R14the same or different, -

hydrogen or an unbranched or branched acyl with 1 to 8 carbon atoms, R6- hydrogen, carboxypropyl, unbranched or branched alkoxycarbonyl with 1 to 5 carbon atoms in the CNS part or unbranched or branched alkyl with 1 to 6 carbon atoms, unsubstituted or substituted hydroxy osvetleni or branched alkyl with 1 to 5 carbon atoms, or an unbranched or branched alkyl with 1 to 22 carbon atoms or alkenyl with 2 to 22 carbon atoms, unsubstituted or substituted group of the formula-OR16in which R16is hydrogen, benzyl, or unbranched or branched acyl with 1 to 6 carbon atoms, R7is hydrogen or R6and R7together mean a group of the formula =O, a mixture of their isomers or their individual isomer in free form or in pharmaceutically acceptable salt in an effective amount.

 

Same patents:

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< / BR>
where R denotes a group of the formula Ia

< / BR>
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