Nitrooxyderivatives of fluvastatin, pravastatin, cerivastatin, atovastatin and rosuvastatin as cholesterol-reducing agents with improved anti-inflammatory, antithrombotic, anti-thrombocytic activity

FIELD: chemistry.

SUBSTANCE: invention relates to novel statin derivatives of formula: or its pharmaceutically acceptable salt or stereoisomer, where: X represents -O-, R represents statin residue of formula:

, Y represents a) straight or branched C1-C20alkylene, mainly C1-C10, optionally substituted with one or more OH;

b)

,

where n equals from 0 to 20, and n1 from 1 to 20; on condition that when Y represents b), group -ONO2 is bonded with -(CH2)n1;

g)

,

where X2 represents -O, n3 from 1 to 6, mainly from 1 to 4, R2 represents H or CH3.

EFFECT: obtaining compounds which possess anti-inflammatory, antithrombotic and antithrombocytic activity, which allows to use them for production of medication for reduction of cholesterol and triglycerides levels and/or for increasing HDL-C level.

14 cl, 6 tbl, 9 ex

 

The present invention relates to new derivatives of the statin. In particular, the invention relates to nitro-derivatives of the statin containing their pharmaceutical compositions and their use as holesterin lowering agents as drugs with immunosuppressive properties, antioxidant, antithrombotic and anti-inflammatory activity, acting on endothelial function and for the treatment and/or prevention of acute coronary syndromes, stroke, neurodegenerative diseases such as Alzheimer's and Parkinson's disease, and autoimmune diseases such as multiple sclerosis.

Statins as a class of compounds that include as major components of lovastatin, simvastatin, pravastatin, mevastatin, fluvastatin, atorvastatin, rosuvastatin and tseriwastatina (avastatin). They have a side group, which is structurally similar to HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A). Fluvastatin, atorvastatin, rosuvastatin and tseriwastatina are completely synthetic compounds containing in the side chain heptane acid residues, which are fungal metabolites.

It is known that different statins are inhibitors of HMG-CoA-reductase, the enzyme that catalyzes an early, limiting the speed stage of the biosynthesis cholesteremia, lower the t, the level of triglycerides and is an indicator of increased levels of HDL-C (P.O.Bonetti et al., European Heart Journal (2003), 24, 225-248).

However, it is also known that statins adverse effects, such as, for example, hepatopathy possible carcinogenesis, muscular side effects and myopathy.

The object of the present invention is new derivatives of statins, which are not only able to eliminate side effects associated with these compounds, but also have superior pharmacological activity. Unexpectedly found that nitro-derivatives statin have improved profile compared with the natural statins as from the point of view of the breadth of pharmacological activity, and from the point of view of tolerance. Found that nitro-derivatives of the statin of the present invention exhibit strong anti-inflammatory, antithrombotic and antiplatelet activity and can be used in the future to reduce the levels of cholesterol and triglycerides, and to increase levels of HDL-C and for the treatment and/or prevention of acute coronary syndromes, stroke, peripheral vascular disorders such as peripheral ischemia, and disorders associated with endothelial dysfunction, such as vascular complications in diabetes and atherosclerosis. They can also be used for the treatment of neurodegenerative and autoimmune diseases, such as Alzheimer's disease, Parkinson is a, and multiple sclerosis.

The object of the present invention are nitro-derivatives statin General formula (I) and their pharmaceutically acceptable salts or stereoisomers

where R the rest of the statin below Y means of a suitable linking group and X as follows.

In accordance with the present invention, the remainder of the statin R in the formula (I) are selected from the group consisting of pravastatin, fluvastatin, tseriwastatina, rosuvastatin and atorvastatin.

Mainly in the General formula (I) R, X and Y have the following meanings: X is-O-, -S-, -NH - or-other1-, R1is a straight or branched alkyl with 1-10 carbon atoms, predominantly CH3;

R represents

or

Y signifies the bivalent radical having the following meanings:

a)

- straight or branched C1-C20alkylen, mainly C1-C10, optionally substituted by one or more substituents selected from the group consisting of: halogen atoms, hydroxy, -ONO2or T0where T0is-CO(O)(C1-C10alkyl)-TNA2or-O(C1-C10alkyl)-ONO2;

- cycloalkyl with 5-7 carbon atoms in cycloalkylation ring, this ring possibly substituted side chains T, where T is a straight or branched alkyl of 1-10 carbon atoms, predominantly CH3;

b)

c)

where n is from 0 to 20, and n1from 1 to 20;

d)

where n1as indicated above, and n2from 0 to 2;

X1=-OCO-or-COO -, and R2means N or CH3;

e)

where

n1n2, R2and X1as stated above;

Y1means-CH2-CH2- or-CH=CH-(CH2)n2-;

f)

where n1and R2as indicated above, R3means N or PINES3;

provided that when Y is chosen from divalent radicals indicated under b)-f), the group-ONO2associated with -(CH2)n1;

g)

where X2means-O - or-S-, n3from 1 to 6, mostly from 1 to 4, R2as stated above;

h)

where n4from 0 to 10;

n5from 1 to 10;

R4, R5, R6, R7are the same or different, represent H or straight or branched C1-C4-alkyl, preferably R4, R5, R6, R7mean N;

where group-ONO2 is associated with

where n5as stated above;

Y2is a 5-6-membered heterocyclic, saturated, unsaturated or aromatic ring containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from:

,,,,,

,,,,,

,,

The term “C1-C20alkylen” here means a straight or branched hydrocarbon chain C1-C20mainly having from 1 to 10 carbon atoms, such as methylene, ethylene, propylene, isopropylene, n-butylene, pentile, n-hexylen and the like.

The term “C1-C10alkyl” means here straight or branched alkyl groups containing from one to ten carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, octyl and the like.

The term “cycloalkyl” here means a ring having 5 to 7 carbon atoms, including, but not limited to cyclopentyl, cyclohexyl optionally substituted side chains such as straight or branched (C1-C10)-alkyl, mainly CH3.

The term “heterocyclic” means here a saturated, unsaturated or aromatic 5-6 membered ring containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, such as, for example, pyridine, pyrazin, pyrimidine, pyrrolidine, morpholine, imidazole and the like.

Another aspect of the present invention is the use of compounds of formula (I) in combination with at least a compound used to treat cardiovascular diseases selected from the group consisting of: inhibitors of ATP antagonists of angiotensin II receptor, beta-adrenergic blockers, blockers calcium channel, antithrombotic means, such as aspirin, nitrosated inhibitors of ATP, nitrosated receptor antagonists of angiotensin II, nitrosated beta-adrenergic blockers and nitrosated aspirin.

Suitable inhibitors of ATP antagonists of angiotensin II receptor, beta-adrenergic blockers, - blockers, calcium channel, antithrombotic means are described in the literature, for example, in The Merck Index (13thedition).

Suitable nitrosated compounds described in WO 98/21193 and WO 97/16405.

The above compounds can destinations shall be simultaneously or sequentially.

The present invention relates also to pharmaceutical kits comprising one or more containers filled with one or more compounds and/or compositions of the present invention and one or more of the above substances used for the treatment of cardiovascular diseases.

As indicated above, the invention also includes pharmaceutically acceptable salts of compounds of formula (I) and their stereoisomers.

Compounds of the present invention, containing in the molecule capable of forming salts of the nitrogen atom, can be converted into the corresponding salts by reaction with the appropriate organic or inorganic acid in an organic solvent such as acetonitrile or tetrahydrofuran.

Examples of organic acids are: oxalic, tartaric, maleic, succinic, citric acid. Examples of inorganic acids are nitric, hydrochloric, sulfuric, phosphoric acid.

Preferred are the salts of nitric acid.

Compounds of the present invention, having one or more asymmetric carbon atoms can exist as optically pure enantiomers, pure diastereomers, enantiomeric mixtures, diastereomeric mixtures, racemic enantiomeric mixtures, racemates or racemic mixtures. In the scope of the invention also includes the all possible isomers, stereometry compounds of formula (I) and mixtures thereof.

Preferred compounds of formula (I) are the following, where

X is-O - or-S-;

R represents the residue of statin above;

Y represents a bivalent radical having the following meanings:

a)

- straight or branched C1-C10alkylene, optionally substituted T0where T0has the above values;

b)

c)

where n is from 0 to 5, and n1from 1 to 5;

d)

where n1as indicated above, and n2from 0 to 2;

X1=-OCO - or-COO -, and R2means N or CH3;

e)

where n1n2, R2and X1as stated above;

Y1means-CH=CH-;

f)

where n1and R2means N or CH3, R3means N or PINES3;

provided that when Y is chosen from divalent radicals indicated under b)-f), the group-ONO2associated with -(CH2)n1;

g)

where X2means-O - or-S-, n31 to 4, mainly 1, R2means a hydrogen atom or CH3;

h)

where n4from 0 to 3;

n51 to 3;

R4, R5, R6, R7are the same and are H;

and where the group-ONO2associated with

;

Y2represents a 6-membered saturated, unsaturated or aromatic heterocyclic ring containing one or more nitrogen atoms and selected from, for example,

,,,,;

In accordance with the present invention, the preferred compounds are the following:

4-(nitroxy)butyl ester of fluvastatin,

4-(nitroxymethyl)benzyl ester of fluvastatin,

3-(nitroxymethyl)benzyl ester of fluvastatin,

2-(nitroxymethyl)benzyl ester of fluvastatin,

4-(nitroxymethyl)phenyl ester of fluvastatin,

3-(nitroxymethyl)phenyl ester of fluvastatin,

2-(nitroxymethyl)phenyl ester of fluvastatin,

2-[2'-(nitroxy)ethyloxy] ethyl ester of fluvastatin, corresponding to the formula:

2-methoxy-4-[[4'-(nitroxy)butyl]TRANS-2-propenyloxy]phenyl ester of fluvastatin, corresponding to the formula:

4-(nitroxy)butyl ether pravastatin,

4-(nitroxymethyl)benzyl ether of pravastatin,

3-(nitroxymethyl)Ben is silt ether pravastatin,

2-(nitroxymethyl)benzyl ether of pravastatin,

4-(nitroxymethyl)phenyl ether pravastatin,

3-(nitroxymethyl)phenyl ether pravastatin,

2-(nitroxymethyl)phenyl ether pravastatin,

2-[2'-(nitroxy)ethyloxy]ethyl ester pravastatin corresponding to the formula:

2-methoxy-4-[[4'-(nitroxy)butyl]TRANS-2-propenyloxy]phenyl ester of pravastatin corresponding to the formula:

4-(nitroxy)butyl ether tseriwastatina,

4-(nitroxymethyl)benzyl ether tseriwastatina,

3-(nitroxymethyl)benzyl ether tseriwastatina,

2-(nitroxymethyl)benzyl ether tseriwastatina,

4-(nitroxymethyl)phenyl ether tseriwastatina,

3-(nitroxymethyl)phenyl ether tseriwastatina,

2-(nitroxymethyl)phenyl ether tseriwastatina,

2-[2'-(nitroxy)ethyloxy]ethyl ester tseriwastatina corresponding to the formula:

2-methoxy-4-[[4'-(nitroxy)butyl]TRANS-2-propenyloxy]phenyl ether tseriwastatina corresponding to the formula:

4-(nitroxy)butyl ester of atorvastatin

4-(nitroxymethyl)benzyl ester of atorvastatin

3-(nitroxymethyl)benzyl ester of atorvastatin

2-(nitroxymethyl)benzyl ester of atorvastatin

4-(nits is oxymethyl)phenyl ester of atorvastatin

3-(nitroxymethyl)phenyl ester of atorvastatin

2-(nitroxymethyl)phenyl ester of atorvastatin

2-[2'-(nitroxy)ethyloxy]ethyl ester of atorvastatin corresponding to the formula:

2-methoxy-4-[[4'-(nitroxy)butyl]TRANS-2-propenyloxy]phenyl ester of atorvastatin corresponding to the formula:

4-(nitroxy)butyl ester of rosuvastatin,

4-(nitroxymethyl)benzyl ester of rosuvastatin,

3-(nitroxymethyl)benzyl ester of rosuvastatin,

2-(nitroxymethyl)benzyl ester of rosuvastatin,

4-(nitroxymethyl)phenyl ester of rosuvastatin,

3-(nitroxymethyl)phenyl ester of rosuvastatin,

2-(nitroxymethyl)phenyl ester of rosuvastatin,

2-[2'-(nitroxy)ethyloxy]ethyl ester of rosuvastatin, corresponding to the formula:

2-methoxy-4-[[4'-(nitroxy)butyl]TRANS-2-propenyloxy]phenyl ester of rosuvastatin, corresponding to the formula:

As described above, an object of the present invention are also pharmaceutical compositions containing at least a compound of the present invention of formula (I) together with non-toxic commonly used in pharmaceutical adjuvants and/or carriers.

Prescribed daily dose of active ingredient m which may be a single dose or this effective amount can be divided into several small doses appointed during the day. Usually the total daily can range from 50 to 500 mg. dosage regimen and frequency assignments for the treatment of the above diseases, the compounds of the present invention and/or pharmaceutical compositions of the present invention should be selected according to various factors, including, for example, age, body weight, sex and condition of the patient as well as severity of the disease, the mode of appointment, pharmacological circumstances and possible concomitant therapy with other drugs. In some cases, the dose levels may be lower or higher than the above interval and/or more fit, are determined by the physician and the picture of the disease.

Compounds of the present invention may be administered orally, parenterally, rectally or topically, by inhalation or in the form of aerosol compositions optionally may contain conventional pharmaceutically acceptable carriers, adjuvants and fillers. Local designation may also include transdermal patches, bandages or device for electophoresis. The term “parenteral” includes subcutaneous injections, intravenous, intramuscular, vnutrigrudne injection or infusion technique.

Injectable preparations, for example a sterile aqueous or oily suspensions, can be formed with Zvezdnyi, used in this field dispersing or wetting agents and suspendresume agents. Sterile injectable preparations can be in the form of sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluent or solvent. Acceptable carriers include water, ringer's solution and isotonic sodium chloride. In addition, there may be used a sterile, fixed oils are commonly used as a solvent or suspendida environment. For these purposes may be any light non-volatile oils, including synthetic mono or diglycerides, in addition, in the manufacture of injectable forms are used fatty acids such as oleic acid.

Suppositories for rectal destination medicinal substance can be prepared by mixing the active ingredient with suitable, not causing irritation excipients, such as cocoa butter and polyethylene glycols.

Solid dosage forms for oral use can include capsules, tablets, pills, powders, granules and gels. In such solid dosage forms the active substance can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms in conventional practice may also include extra is leitlinie substances, other than inert diluents, for example, lubricants such as magnesium stearate. In the case of capsules, tablets or pills dosage forms also contain buffering agents.

Liquid dosage forms for oral use can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing commonly used in this field inert solvents, such as water. Such compositions may also contain adjuvants, such as moistening agents, emulsifiers and suspendresume agents, sweeteners, flavorings, etc.

As mentioned above, the new nitro-derivatives of the stronger statins lower levels of lipids, have increased anti-inflammatory, antithrombotic and antiplatelet effect compared to natural statins. Moreover, they can be effective in other pathologies, such as acute coronary syndromes, stroke, peripheral vascular disorders such as peripheral ischemia, all disorders associated with endothelial dysfunction, such as vascular complications in diabetes and atherosclerosis, neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), autoimmune diseases such as multiple sclerosis.

The study of vascular tone.

The ability of the nitro-derivatives of the article is as to induce vasorelaxation compared to natural statins, investigated in vitro on isolated preparations of the thoracic aorta of a rabbit(Wanstall J.. et al., Br.J.Pharmacol, 134: 463-472, 2001). Male new Zealand rabbits were anestesiologi by thiopental sodium (50 mg/kg, I/V), was scarificial by bleeding, then opened the chest and dissect the aorta. A separate ring preparations of the thoracic aorta (4 mm) were placed in a small chamber organs (5 ml) with saline solution (DCF) at 37°C. the composition of the SDF (mm): NaCl 130, NaHCO314,9,

KN2PO41,2, MgSO4of 1.2, HEPES 10, CaCl2, ascorbic acid 170 and glucose of 1.1 (95% O2/5% CO2; pH 7.4). Each ring was placed in 5 ml of camera bodies under the passive partial pressure of 2 g. Isomeric partial pressure was recorded using a Grass-transducer (Grass FT03)attached to the system BIOPAC MP150. The preparations were left for equilibration for 1 hour, then submaximal squeezed with noradrenaline (NA, 1 μm) and, when the contraction was stable, was added to acetylcholine (ACh, 10 μm). Relaxation response to acetylcholine indicates the presence of a functionally active endothelial. After attaining a stable pre-reduction received cumulative curve dose-response for one of the two agents, relaxing blood vessels, in the presence of functionally active endothelial. The time intervals between the various the concentrations were based on time, necessary for achieving complete response. In addition, the effect of soluble inhibitor guanylyl cyclase ODQ (1-N-(1,2,4)-oxadiazol(4,3-a)cinoxacin-1-he) reaction of the expansion caused by these compounds was checked by pre-incubation of aortic rings with ODQ (10 PM) for 20 minutes. Reactions to agents, relaxing blood vessels, measured from the horizontal part NA reduction. IC50(the concentration which provides 50% elimination of NA reduction) was interpolable from points on the curve “relaxing agent-response depending on the logarithm of the molar concentration of the compounds.

During the experimental period the plateau obtained with NA, was stable without significant spontaneous reduction reduction in aortic rings. Under these experimental conditions, natural statins did not lead to a relaxation of up to 30 μm, the curve did not differ from the curve obtained in the presence of one of the filler.

As shown in the following Table 1, the nitro-derivatives according to this invention had the ability to cause relaxation dependent on concentration. Moreover, in experiments conducted in the presence of ODQ (10 μm), sosudorasshiryayuschee response to all tested drugs were ingibirovany.

Table
ConnectionIC50(μm) ± standard error of the mean
Pravastatin>30
Connection example 12,4±0,6
Fluvastatin>30
The compound of example 313,4±3,5
The compound of example 48,7±3,3

The effects of derivative necrostatin on cascades of inflammation in vitro

The experiments were conducted using the monocyte-macrophage cell line RAW264.7. Cells stimulated in the presence of LPS (1 μg/ml) for 8 hours (pravastatin and derived) or 16 hours (fluvastatin, atorvastatin and derivatives). After incubation, the cells were collected in lytic buffer and measured the protein content. Performed Western blot analysis of inducible iNOS protein and MOR2(proceeding of the inflammatory process). The results, presented in Table 2, expressed as % reduction in optical density of each option compared with samples treated with LPS. Negative results mean improvement compared to the single LPS.

Table 2
ConnectionConcentration (µm)iNOS (% reduction compared LPS)SOH (% reduction compared to LPS)
Fluvastatin10was 14.8±-2,8+3,7
Connection example 31044,8±11,953,9±6,1
Connection example 41022,4±9,619,4±6,5
Pravastatin1004,7±3,626,9±7,9
Connection example 110055,2±11,8of 74.9±4,4
Atorvastatin1020±14-
Connection example 71045±9-

Nitro-derivatives flava Tatina, pravastatin and atorvastatin on cell line RAW264.7 have a significant inhibitory effect on the expression of proteins such as SOH and iNOS, which are relevant to the process of inflammation. On the contrary, these effects are not defined or are weak at the source connection.

Studying the effects of nitro-derivatives of pravastatin with peripheral vascular disease.

Angiogenesis is a primary response to local tissue hypoxia and probably participates in the restoration of blood flow in ischemic diseases, such as acute coronary syndromes and occlusal disease peripheral vascular. The ability of the nitro-derivatives of pravastatin (compound of example 1) to inhibit the process of angiogenesis was evaluated using in vivo model of ischemic hind limbs of mice, as described previously (Emanueli et al., Circulation 103, 125-132, 2001). Briefly, male mice CDl (Charles River, Italy) at two months of age were divided into three groups randomly (n=20 each), animal feed contained: 1) pravastatin (40 mg/kg), 2) nitro-derivatives of pravastatin (48 mg/kg), 3) filler (normal feed). After 3 days, mice analizirovali and causing ischemia of the left rear leg by electrocautery upper part of the femoral artery. Treatment continued over the next 2 weeks after surgery. Measured systolic blood on the lead 7 and day 14 by applying the cuff on the tail. The outcome of the disease on day 14 was determined by counting the number of dead or missing claws on the paw subjected to ischemia and the incidence of samalpatti. On day 14 after induction of ischemia, the hind limbs shot mouse were fixed by perfusion, both leading muscle coded and subjected to histological analysis. Determined the density of capillaries and arterioles ncap/mm2and nart/mm2).

Table 3
ConnectionThe number of capillaries/mm2in ischemic causes muscleThe number of capillaries/mm2in the contralateral leading muscle
Filler852±32§§685±38
Pravastatin823±42736±40
Connection example 11116±53§§**++660±40

**P<0,01 compared with a filler;++P<0,01 compared with pravastatin;§§P<0,01 compared to conform to what she contralateral group.

As shown in table 3, unlike the parent compound, the compound in this invention have the ability to potentiate the natural reparative capillarization response to ischemia. The results of this study show that the nitro-derivatives contributes to a significant reparative neovascularization and improves clinical outcome in mice with hind limb ischemia caused experimentally.

The influence of the nitro-derivatives of pravastatin on the adhesion of leukocytes in the knockout mice APOE.

The interaction between leukocytes and the vascular endothelium is a key stage of inflammation in the atherogenic process. The ability of the nitro-derivatives of pravastatin (compound of example 1) to inhibit adhesion of leukocytes was investigated ex vivo in mice with atherosclerosis (APOE knockout).

Three groups knockout mice APOE defined doses daily for 5 days was administered pravastatin (40 mg/kg, orally), nitro-derivatives of pravastatin (equimolar dose) or filler, mice were subjected to euthanasia CO2-asphyxia within 1 hour after the last dose.

Leukocytes were isolated from the spleen, centrifuged, erythrocytes (RBC) were literally water. Prepared segments of arteries - the area of the aorta & thoracic aorta dissected longitudinally and arranged side clearance centuries the px. Leukocytes labeled with a radioactive isotope (51SG-cells) were incubated for 30 minutes with segments stimulated by thrombin (10 EML-1 for 10 minutes). The segments were washed with medium and adhesion was determined using a gamma counter.

Table 4
ConnectionApoE K/O mouse leukocyte Adhesion (%) (thoracic aorta)
Filler23,4±5
Pravastatin23,0±6
Connection example 19,3±3*#
*P<0.05 compared with filler;#P<0.05 compared with pravastatin.

As shown in Table 4, unlike the parent compound, the compound in this invention have the ability to reduce the adhesive interaction between the isolated leukocytes and the wall of the blood vessel induced by thrombin, both breeds of mice.

These data demonstrate that the nitro-derivatives has protivoallergennye/anti-inflammatory effects.

The study of antithrombotic action of nitro-derivatives pravastatin is in vivo.

The ability of the nitro-derivatives of pravastatin to inhibit thrombus formation was evaluated in male mice Charles river CD-1 (20-25 g) through the introduction of pravastatin (10 or 20 mg/kg, intraperitoneally), the compound of example 1 (equimolar dose) or filler. After 1-3 hours, the animals were doing the injection U46619 (0.2 mg/kg) (a stable analogue of The) into the tail vein. As described previously (Momi et al., Eur. J.Pharmacol. 397: 177-185, 2000), this dose of agonist leads to death in 80-90% of cases within 3 minutes in the control group. In each experimental session were examined at least 6 animals in each treatment group; the control group was examined at the beginning and end of each experimental session. Protection against thromboembolism induced by the agonist, was expressed

as (1-Tmedicine/Tsaline)×100, where Tmedicinerepresents the mortality rate in mice receiving the drug, and Tsalinerepresents the number of surviving animals from the control group who received only thrombin. The results are expressed as percent protection from pulmonary thromboembolism induced by U46619, compared with the control group.

Table 5
ConnectionAntithrombotic activity is b (%) 1 hour prior to the introduction of substances Antithrombotic activity (%) for 3 hours prior to the introduction of substances
Filler00
Pravastatin
10 mg/kg1510
intraperitoneally
20 mg/kg2520
intraperitoneally
Connection example 1
12 mg/kg30*40*
intraperitoneally
24 mg/kg40*+55*+
intraperitoneally
*P<0.05 compared with control; +P<0.05 compared the structure with pravastatin.

As shown in Table 5, in contrast to the original connection, the connection according to this invention are able to inhibit thrombus formation induced by the action of U46619.

The study of antiplatelet action of nitro-derivatives of pravastatin in vitro.

Platelets are characteristic components of blood clots. The ability of the nitro-derivatives of pravastatin (compound of example 1) to inhibit platelet aggregation was evaluated in vitro on human platelets. Platelet aggregation was measured in 0.25 ml of platelet-rich plasma (PRP) or in samples of platelets, followed by gel-filtration (GFP), as described previously (Vezza R, et al., Blood 73: 2006-2013, 1993). Before the addition of U46619 (agent aggregation, similar Tho) compounds were incubated for 2 minutes at 37°C. Aggregation was carried out for 5 minutes, and measured the maximum amplitude (cm). As the carrier used DMSO (0.05 per cent). Compounds were tested at concentrations in the range from 50 to 200 microns.

Table 6
ConnectionAggregation of platelets (GFP) IC50mcmAggregation of platelets (PRP) IC50mcm
Pravastatin>200 >200
Connection example 1101±1074±7

As shown in Table 6, unlike the parent compound, nitro-derivatives according to this invention are able to inhibit platelet aggregation induced by the action of U46619.

The influence of the nitro-derivatives of pravastatin on the inhibition of the expression of tissue factor in vitro.

Tissue factor (TF) is the main regulator of homeostasis and thrombosis. The ability of the nitro-derivatives of pravastatin (compound of example 1) to inhibit the expression was evaluated on isolated preparations of mononuclear cells (MNC) of human blood. MNC were obtained from fresh blood by centrifugation in a density gradient (Ficoll-Hypaque) and resuspending in serum-free RPMI medium at a concentration of 2-3×l06/ml.

Nitro-derivatives of pravastatin (3-50 μm) or pravastatin (50 μm) was added to the cell suspension prior to exposure to LPS (1 μg/ml). After incubation for 3 hours at 37°C, expression of TF by mononuclear cells (MNC) were evaluated in the following ways:

1) functional analysis of intact cells (Semeraro et al., 1983. Immunology; 50: 529-35); 2) immunological analysis of cell extracts Triton X-100 (Imubind, Instrumentation Laboratory, Milan); 3) RT-PCR (riverchase-PCR) (Rossiello et al. Thromb Haemost 2000; 84: 453-59)./p>

Table 7
ConnectionTF in MNC stimulated LPS
Activity (UE/106cells)§Antigen (ng/mg protein)
Filler (DMSO of 0.1%)178±36,25,0±1,1
Pravastatin (50 μm)189±37,64,4±1,3
The compound of example 1 (50 μm)16±4,9**0,65±0,11**

Data represent the average standard error of measurement of 4-5 experiments.

§Conventional units are calculated from a standard curve constructed with reliegion tissue factor human

**P<0,01 compared with pravastatin and filler.

As shown in Table 7, in contrast to the original connection, the connection according to this invention significantly inhibited the expression of tissue factor induced by LPS (activity and antigen). The results of this study show that the nitro-derivatives exhibits antithrombotic activity.

Following the e examples additionally illustrate the invention, not limiting it.

A common way

Compounds of General formula (I), where X=O, can be obtained

the interaction of the compounds of formula (II)

where M signifies hydrogen or an alkali or alkaline earth metal such as sodium or calcium, with the compound of formula (III)

,

where a represents a group to delete, such as chlorine, bromine, iodine, tosyl or mesyl, chosen from chlorine, bromine, iodine or nitroxy group and Y is as defined above for formula (I), in an inert organic solvent such as N,N'-dimethylformamide, tetrahydrofuran, benzene, toluene, at temperatures from room temperature up to 50°C. the Reaction is stopped after 30 minutes to 24 hours.

The compounds of formula (II) are known, commercially available compounds or can be obtained in accordance with well known methods in the literature. The compounds of formula (III), where And as indicated above and represents CL, Br, I, are commercially available or can be synthesized in accordance with well known from the literature methods.

The compounds of formula (III), where And as indicated above and is ONO2synthesized by the conversion of the compounds of formula (III)where In represents CL, Br, I, in the corresponding nitro-derivatives interaction with a nitrate source such as nitrate is elebra, the lithium nitrate, sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, iron nitrate, zinc nitrate or nitrate of tetraalkylammonium (where alkyl means C1-C10alkyl) in a suitable organic solvent, such as acetonitrile, tetrahydrofuran, methyl ethyl ketone, ethyl acetate, DMF, and the interaction is carried out in darkness at a temperature of from room temperature up to the boiling point of the solvent. The reaction is stopped after 30 minutes to 3 days. Preferred nitrate source is nitrate of silver.

The compounds of formula (I), where X=O, S, NH or NR1, R1as described above, can be obtained by reaction of compounds of formula (II), where M represents hydrogen, in the presence of a dehydrating agent with the compound of the formula (IV)

where Y and as stated above, and D is chosen from NH2, Other1HE or SH, R1as specified above. Preferred dehydrating agents are N,N'-carbonyldiimidazole used in the presence of catalytic amounts of ateleta sodium, DCC, EDAC. The reaction is carried out in an inert organic solvent such as N,N'-dimethylformamide, tetrahydrofuran, benzene, toluene, polygalacturonase aliphatic hydrocarbons, at temperatures from -50°C to 50°C from 30 minutes to 24 hours.

The compounds of formula (IV), where D is as above ive represents CL, VG, I, are commercially available or can be synthesized in accordance with well known from the literature methods.

For example, they can be obtained from the corresponding hydroxy of the formula (V) D-Y-OH, by reaction with thionyl or oxalyl chloride, halides, RIIIor RVmesyl chloride, tosyl chloride and an inert solvent, such as toluene, chloroform, DMF, etc.

The compounds of formula (IV), where D is as above and is ONO2can be obtained by the reaction of compounds of formula (IV), where a is CL, Br, I with a nitrate source as above. In addition, the compounds of formula (IV), where In is ONO2can be obtained by interaction of the corresponding hydroxyl compounds of the formula (V) with nitric acid and acetic anhydride at a temperature from -50°C to 0°C in accordance with well-known literature methods.

Example 1

Synthesis of 4-(nitroxy)butyl ether [1S-[1µ(ľs*,ľs*),2µ,6µ,8µ-(R*),8aµ]]-1,2,6,7,8,8A-hexahydro-µ,µ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutanoic)-1-naphthalenemethanol acid (4-(nitroxy)butyl ether pravastatin).

a) 4-Bromatology ether [1S-[1µ(ľs*,ľs*),2µ,6µ,8µ-(R*),a]]-1,2,6,7,8,8A-hexahydro-µ,µ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutanoic)-1-naphthalenemethanol acid

To a solution of pravastatin sodium (a 9.25 g, 21 m is ol) in N,N-dimethylformamide (70 ml) was added dropwise a mixture of 1,4-dibromobutane (3,68 ml, 31 mmol) in N,N-dimethylformamide (30 ml). The reaction mixture was stirred at room temperature for 24 hours. Then the solution is treated with water and diethyl ether, the organic layers are dried with sodium sulfate and concentrated under reduced pressure. The residue is purified on a flash chromatography, using as eluent n-hexane/ethyl acetate 3/7. Get listed in the title compound as a white powder (7.8 g).

b) 4-(Nitroxy)-butyl ether [lS-[1µ(ľs*,ľs*),2µ,6µ,8µ-(R*),8aµ]]-1,2,6,7,8,8A-hexahydro-µ,µ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutanoic)-1-naphthalenemethanol acid

The solution obtained as described in (a) compound (7.7 g, 14 mmol) and silver nitrate (3.5 g, 21 mmol) in acetonitrile (90 ml) was stirred at 40°C in the dark for 48 hours. The formed precipitate (silver salt) is filtered off and the solvent evaporated under vacuum. Then the residue is purified on a flash chromatography, using as eluent n-hexane/ethyl acetate 3/7. Get listed in the title compound as a white powder (3.7 g), melting at 63°C.

1H-NMR: µ (CDCl3) 6.00 (1H, m); 5.88 (1H, m); 5.53 (1H, s); 5.40 (1H, s); 4.51 (2H, t); 4.40 (1H, m); 4.26 (1H, m); 4.15 (2H, t); 3.78 (1H, m); 2.60-2.23 (6H, m); 1.8-1.20 (14H, m); 1.10 (3H, d); 0.87 (6H, t).

Example 2

Synthesis of 4-(nitroxymethyl)benzyl ether [1S-[1µ(ľs*,ľs*),2µ,6µ,8µ-(R*),8aµ]]-1,2,6,7,8,8A-hexahydro-µ,µ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutanoic)-1-naphthalenemethanol acid (4-(nits is oxymethyl)benzyl ether of pravastatin).

a) 4-(Chloromethyl)benzyl ether [1S-[1µ(ľs*,ľs*),2µ,6µ,8µ-(R*),a]]-1,2,6,7,8,8A-hexahydro-µ,µ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutanoic)-1-naphthalenemethanol acid

To a solution of µ,µ1-dichloro-p-xylene (5.5 g, 31 mmol) in N,N-dimethylformamide (70 ml) is added by portions pravastatin sodium (7 g, 15 mmol). The reaction mixture was stirred at room temperature for 24 hours. Then the resulting solution is treated with water and diethylacetal, organic layers are dehydrated with sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel, using as eluent n-hexane/ethyl acetate 1/1. Get listed in the title compound as a white powder (5.5 g), which is used in the next stage without purification.

b) 4-(Nitroxymethyl)-benzyl ester [1S-[1µ(ľs*,ľs*),2µ,6µ,8µ-(R*),8aµ]]-1,2,6,7,8,8a-hexahydro-µ,µ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutanoic)-1-naphthalenemethanol acid

The solution obtained as described in (a) compound (5.5 g, 7.7 mmol) and silver nitrate (2.5 g, 15 mmol) in acetonitrile (60 ml) was stirred at 60°C in the dark for 48 hours. The formed precipitate (silver salt) is filtered off and the solvent evaporated under vacuum. Then the residue is purified on a flash chromatography, using as eluent n-hexane/ethyl acetate 1/1. Get the specified header joint is in the form of a white powder (1.6 g), melting at 80-82°C.

1H-NMR(CDCl3): 7.39 (4H, m); 5.98 (1H, m); 5.86 (1H, m); 5.54 (1H, s); 5.42 (3H, s); 5.16 (2H, s); 4.40 (1H, m); 4.27 (1H, m); 3.80 (1H, m); 2.52 (3H, m); 2.45-2.25 (3H, m); 1.74-1.10 (10H, m); 1.10 (3H, d); 0.87 (6H, t).

Example 3

Synthesis of 4-(nitroxy)butyl ether [R*,S*-(E)]-7-[3-(4-forfinal)-1-(1-methylethyl)-1H-indol-2-yl] - for 3,5-dihydroxy-6-heptane acid (4-(nitroxy)butyl ester of fluvastatin)

a) 4-Bromatology ether [R*,S*-(E)]-7-[3-(4-forfinal)-1-(1-methylethyl)-1H-indol-2-yl] - for 3,5-dihydroxy-6-heptane acid

To a solution of 1,4-dibromobutane (4,1 ml, 34 mmol) in N,N-dimethylformamide (60 ml) was added dropwise a mixture of fluvastatin sodium (5 g, 11 mmol) in N,N-dimethylformamide (40 ml). The reaction mixture was stirred at room temperature for 24 hours. Then the resulting solution is treated with water and diethylacetal, organic layers are dehydrated with sodium sulfate and concentrated under reduced pressure. The residue is purified on a flash chromatography, using as eluent n-hexane/isopropanol 8,5/a 1.5. Get listed in the title compound as a yellow oil (4.7 g), which is used in the next stage without purification.

b) 4-(Nitroxy)butyl ether [R*,S*-(E)]-7-[3-(4-forfinal)-1-(1-methylethyl)-1H-indol-2-yl] - for 3,5-dihydroxy-6-heptane acid

The solution obtained as described in (a) compound (4.7 g, 8.5 mmol) and silver nitrate (2.9 g, 17 mmol) in AC is onitrile (60 ml) was stirred at 60°C in the dark for 48 hours. The formed precipitate (silver salt) is filtered off and the solvent evaporated under vacuum. Then the residue is purified on a flash chromatography, using as eluent n-hexane/ethyl acetate 1/1. Get the desired product as a white powder (0.5 g), melting at 112°C.

1H-NMR µ (DMSO):7.69 (1H,d); 7.43 (3H,m); 7.27 (2H,t); 7.25 (1H,t); 7.03 (1H,t); 6.65 (1H,d); 5.75 (1H,dd); 4.98 (1H,d); 4.90 (1H,m); 4.78 (1H,d); 4.50 (2H,t); 4.25 (1H,m); 4.09 (2H,t); 3.9 (1H,m); 2.4 (2H,m); 1.67 (4H,m); 1.61 (6H,d); 1.42 (2H,m).

Example 4

Synthesis of 4-(nitroxymethyl)benzyl ester [R*,S*-(E)]-7-[3-(4-forfinal)-1-(1-methylethyl)-1H-indol-2-yl] - for 3,5-dihydroxy-6-heptane acid (4-(nitroxymethyl)benzyl ester of fluvastatin)

a) 4-(Chloromethyl)benzyl ester [R*,S*-(E)]-7-[3-(4-forfinal)-1-(1-methylethyl)-1H-indol-2-yl] - for 3,5-dihydroxy-6-heptane acid

To a solution of-dichloro-p-xylene (10 g, 57 mmol) in N,N-dimethylformamide (60 ml) was added dropwise a mixture of fluvastatin sodium (10 g, 23 mmol) in N,N-dimethylformamide (80 ml). The reaction mixture was stirred at room temperature for 24 hours. Then the resulting solution is treated with water and ethyl acetate, the organic layers are dehydrated with sodium sulfate and concentrated under reduced pressure. The residue is purified on a flash chromatography, using as eluent n-hexane/ethyl acetate 1/1. After crystallization from n-hexane receive specified in the header soy is inania in the form of a white powder (9.4 g).

b) 4-(Nitroxymethyl)benzyl ester [R*,S*-(E)]-7-[3-(4-forfinal)-1-(1-methylethyl)-1H-indol-2-yl] - for 3,5-dihydroxy-6-heptane acid

The solution obtained as described in (a) compound (9.4 g, 17 mmol) and silver nitrate (10.6 g, 63 mmol) in acetonitrile (180 ml) was stirred at 50°C in the dark for 24 hours. The formed precipitate (silver salt) is filtered off and the solvent evaporated under vacuum. Then the residue purified flash chromatography, using as eluent n-hexane/ethyl acetate 4/6. Get the desired product as a white powder (4 g), melting at 103-104°C.

1H-NMR(DMSO): 7.65 (1H, d); 7.42 (7H, m); 7.22 (2H, t); 7.15 (1H, t); 7.03 (1H, t); 6.64 (1H, d); 5.75 (1H, dd); 5.51 (2H, s); 5.12 (2H, s); 4.98 (1H, d); 4.88 (1H, t); 4.84 (1H, d); 4.27 (1H, t); 3.94 (1H, t); 2.4-2.6 (2H, m); 1.4-1.7 (2H, M); 1.57 (6H, d).

Example 5

Synthesis of 3-(nitroxymethyl)benzyl ester [R*,S*-(E)]-7-[3-(4-forfinal)-1-(1-methylethyl)-1H-indol-2-yl] - for 3,5-dihydroxy-6-heptane acid (3-(nitroxymethyl)benzyl ester of fluvastatin)

a) 3-(Chloromethyl)benzyl ester [R*,S*-(E)]-7-[3-(4-forfinal)-1-(1-methylethyl)-1H-indol-2-yl] - for 3,5-dihydroxy-6-heptane acid

To a solution of-dichloro-p-xylene (0.95 g, 5.4 mmol) in N,N-dimethylformamide (25 ml) was added dropwise a mixture of fluvastatin sodium (0,79 g, 1.8 mmol) in N,N-dimethylformamide (25 ml). The reaction mixture was stirred at room temperature for 24 hours and Then the resulting solution is treated with water and ethyl acetate, the organic layers are dehydrated with sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel, using as eluent n-hexane/ethyl acetate 1/1, getting mentioned in the title compound (0,41 g).

b) 3-(Nitroxymethyl)benzyl ester [R*,S*-(E)]-7-[3-(4-forfinal)-1-(1-methylethyl)-1H-indol-2-yl] - for 3,5-dihydroxy-6-heptane acid

The solution obtained as described in (a) compound (0.4 g, 0.7 mmol) and silver nitrate (0.36 g, 2.1 mmol) in acetonitrile (30 ml) was stirred at 45°C in the dark for 24 hours. The formed precipitate (silver salt) is filtered off and the solvent evaporated under vacuum. Then the residue is purified on a flash chromatography, using as eluent methylene chloride/isopropanol 9,5/0,5, receiving 0.2 g of the desired product.

1H-NMR(DMSO): 7.67 (1H, d); 7.47-7.40 (7H, m); 7.25-7.10 (3H, m); 7.05 (1H, t); 6.62 (1H, d); 5.72 (1H, dd); 5.49 (2H, s); 5.13 (2H, s); 5.00-4.84 (3H, m); 4.27 (1H, m); 3.95 (1H, m); 2.60-2.35 (2H, m); 1.58 (6H, d); 1.70-1.45 (2H, m).

Example 6

Synthesis of 2-(nitroxymethyl)benzyl ester [R*,S*-(E)]-7-[3-(4-forfinal)-1-(1-methylethyl)-1H-indol-2-yl] - for 3,5-dihydroxy-6-heptane acid (2-(nitroxymethyl)benzyl ester of fluvastatin)

a) 2-(Chloromethyl)benzyl ester [R*,S*-(E)]-7-[3-(4-forfinal)-1-(1-methylethyl)-1H-indol-2-yl] - for 3,5-dihydroxy-6-heptane acid

To a solution of-dichloro-p-KS is Lola (1.5 g, 5.4 mmol) in N,N-dimethylformamide (15 ml) was added dropwise a mixture of fluvastatin sodium (1.5 g, 8.6 mmol) in N,N-dimethylformamide (15 ml). The reaction mixture was stirred at room temperature in the dark for 24 hours. Then the resulting solution is treated with water and ethyl acetate, the organic layers are dehydrated with sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel, using as eluent n-hexane/ethyl acetate 6/1, getting mentioned in the title compound (0.97 g).

b) 2-Nitroxymethyl)benzyl ester [R*,S*-(E)]-7-[3-(4-forfinal)-1-(1-methylethyl)-1H-indol-2-yl] - for 3,5-dihydroxy-6-heptane acid

The solution obtained as described in (a) compound (0.97 g, 1.7 mmol) and silver nitrate (1.3 g, 7.6 mmol) in acetonitrile (40 ml) was stirred at 45°C in the dark for 24 hours. The formed precipitate (silver salt) is filtered off and the solvent evaporated under vacuum. Then the residue is purified on a flash chromatography, using as eluent methylene chloride/isopropanol to 9.5/0.5, the receiving of 0.42 g of the desired product as a yellow powder.

1H-NMR(DMSO): 6.527.47-7.30 (7H, m); 7.24-7.147.03 (1H, t); 6.27 (1H, d); 5.70 (1H, dd); 5.66 (2H, s); 5.22 (2H, s); 4.98 (1H, m); 4.84 (1H, t); 4.82 (1H, d); 4.30 (1H, m); 3.902.40 (2H, m); 1.58 (6H, d); 1.40 (2H, m).

Example 7

Synthesis of 4-(nitroxy)putilovo the ether (µR,µR)-2(4-forfinal)-µ,µ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1-H-pyrrol-1-heptane acid (4-(nitroxy)butyl ester of atorvastatin).

a) 4-(Bromatology ether (µR,µR)-2(4-forfinal)-µ,µ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1-H-pyrrol-1-heptane acid

To a solution of 1,4-dibromobutane (0,34 ml, 2,884 mmol) in N,N-dimethylformamide (19 ml) was added dropwise a mixture of atorvastatin calcium (0,83 g to 0.72 mmol) in N,N-dimethylformamide (10 ml). The reaction mixture was stirred at room temperature for 24 hours. Then the resulting solution is treated with water and diethyl ether, the organic layers are dehydrated with sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel, using as eluent n-hexane/ethyl acetate 6/4, getting mentioned in the title compound (0.97 g) as a white solid residue.

b) 4-(Nitroxy)butyl ether (µR,µR)-2(4-forfinal)-µ,µ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1-H-pyrrol-1-heptane acid

The solution obtained as described in (a) compound (0.25 g, 0.36 mmol) and silver nitrate (or 0.38 g, 2.2 mmol) in acetonitrile (10 ml) was stirred at 50°C in the dark for 21 hours. The formed precipitate (silver salt) is filtered off and the solvent evaporated under vacuum. Then the resulting residue is purified by chromatography on silica gel, using as eluent n-hexane/ethyl acetate 1/1, receiving of 0.41 g of the desired product as a yellow powder.

1H-NMR (DMSO): 9.80 (1H, s); 7.51 (2H, d); 7.26-7.19 (6N, m); 7.09-6.95 (6H, m); 4.73 (1H, d); 4.61 (1H, d); 4.54 (2H, t); 4.04. (2H, t); 4.00-3.70 (3H, m); 3.50 (1H, m); 3.22 (1H, m); 2.40 (1H, dd); 2.25 (1H, dd); 1.80-1.10 (8H, m); 1.38 (6H, d).

Following examples 1-7 on the basis of appropriate reagents and using tseriwastatina and rosuvastatin instead of pravastatin, fluvastatin and atorvastatin.

Example 8

Synthesis of 2-[2-(nitroxy)ethoxy]ethyl ester (βR,βR)-2(4-forfinal)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-heptane acid 2-[2-(nitroxy)ethoxy] ethyl ester of atorvastatin).

a) 2-[2-(bromo)ethoxy]ethyl ester (βR,δR)-2(4-forfinal)-β,δ-dihydroxy-5(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-heptane acid

To a solution of 2-bromatologia ether (0,65 ml, 5,19 mmol) in N,N-dimethylformamide (8 ml) was added dropwise a mixture of atorvastatin calcium (1.5 g, of 1.30 mmol) in N,N-dimethylformamide (10 g). The reaction mixture was stirred at room temperature for 72 hours. Then the resulting solution is treated with water-ethyl acetate, the organic layers are dehydrated with sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel, using as eluent n-hexane/ethyl acetate 6/4, getting mentioned in the title compound (0.40 g).

a) 2-[2-(nitroxy)ethoxy]ethyl ester (βR,δR)-2(4-forfinal)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl--[(phenylamino)carbonyl]-1H-pyrrol-1-heptane acid

The solution obtained as above compounds (a 0.30 g, 0.42 mmol) and silver nitrate (0,37 g of 2.18 mmol) in acetonitrile (5 ml) is heated in a microwave setting (120°C, 25 minutes). The formed precipitate (silver salt) is filtered off and the solvent evaporated under vacuum. Then the residue is purified with flash chromatography using as eluent n-hexane/ethyl acetate 4/6, receiving (0.08 g) of the desired product as a white powder.

1H-NMR δ (CDCl3): 7.25-7.12 (M, m); 7.15-6.94 (5H, m); 6.88 (1H, s); 4.63 (2H, s); 4.41-4.05 (4H, m); 4.04-3.86 (1H, m); 3.84-3.68 (5H, m); 3.67-3.49 (3H, m); 2.47 (2H, d); 1.82-1.42 (10H, m).

Example 9

Synthesis of 4-(nitroxymethyl)benzyl ether (βR,δR)-2(4-forfinal)-β,δ-dihydroxy-5-(1-methylethyl)-3-[(phenylamino)carbonyl]-1H-pyrrol-1-heptane acid

a) 4-(chloromethyl)benzyl ether (βR,δR)-2(4-forfinal)-β,δ-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-heptane acid

To a solution of,-dichloro-p-xylene (3.98 g, 22,75 mmol) in N,N-dimethylformamide (40 ml) was added dropwise a mixture of atorvastatin calcium (of 4.38 g of 3.80 mmol) in dimethylformamide (20 ml). The reaction mixture was stirred at room temperature for 48 hours. Then the resulting solution is treated with water and diethyl ether, the organic layers are dehydrated with sodium sulfate and concentrated under reduced giving the situation. The residue is purified by chromatography on silica gel, using as eluent n-hexane/ethyl acetate 1/1, getting mentioned in the title compound (0,80 g) as a white solid residue.

b) 4-(nitroxymethyl)benzyl ether (βR,δR)-2(4-forfinal)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-heptane acid

A solution of the compound obtained above (0,80 g, 1.15 mmol)and silver nitrate (0.29 grams, 1,72 mmol) in acetonitrile (50 ml), stirred at 40°C in the dark for 48 hours and then add a further quantity of silver nitrate (0.10 g, or 0.57 mmol) and the mixture is stirred at 70°C in the dark for 24 hours. The formed precipitate (silver salt) is filtered off and the solvent evaporated under vacuum. Then the residue purified by chromatography on silica gel, using as eluent n-hexane/ethyl 6/4, receiving (0.40 g) of the desired product as a white powder.

1H-NMR δ (DMSO): 9,78 (1H, s); 7,66-7,32 (6N, m); 7,32-6,82 (N, m); to 5.57 (2H, s); 5,12 (2H, s); rate 4.79 (1H, d); 4,63 (1H, d); 4,06-of 3.64 (3H, m); of 3.54 (1H, m); 3,23 (1H, m); of 2.51 with 2.14 (2H, m); 1.85 to 1,18 (10H, m).

1. The compound of General formula (I) or its pharmaceutically acceptable salt or stereoisomer

where X represents-O-,
R represents the residue of statin formula



Y signifies the bivalent is radical, with the following values:
a) straight or branched C1-C20alkylen, mainly C1-C10, optionally substituted by one or more substituents selected from hydroxy,
b)

where n is from 0 to 20, and n1from 1 to 20;
provided that when Y is chosen from divalent radicals indicated under b), group-ONO2associated with -(CH2)n1;
g)

where X2means, n3from 1 to 6, mostly from 1 to 4, R2means N or CH3;

2. The compound of General formula (I) and/or its pharmaceutically acceptable salt or stereoisomer according to claim 1, where
X is-O-;
R represents the residue of a statin according to claim 1;
Y represents a bivalent radical having the following meanings:
a) straight or branched C1-C10alkylen,
b)

where n is from 0 to 5, and n1from 1 to 5;
provided that when Y is chosen from divalent radicals indicated under b), group-ONO2associated with -(CH2)n1;
g)

where X2means, n31 to 4, mainly 1, R2as specified in claim 1;

3. The compound of formula (I) according to claim 1, which is 4-(nitroxy)butyl ether pravastatin, fluvastatin and atorvastatin.

5. The compound of formula (I) according to claim 1, which is 3-(nitroxymethyl)-benzyl ether pravastatin, fluvastatin and atorvastatin.

6. The compound of formula (I) according to claim 1, which is 2-(nitroxymethyl)-benzyl ether pravastatin, fluvastatin and atorvastatin.

7. The compound of formula (I) according to claim 1, which is 4-(nitroxymethyl)-phenyl ester pravastatin, fluvastatin and atorvastatin.

8. The compound of formula (I) according to claim 1, which is 3-(nitroxymethyl)-phenyl ester pravastatin, fluvastatin and atorvastatin.

9. The compound of formula (I) according to claim 1, which is 2- (nitroxymethyl)-phenyl ester pravastatin, fluvastatin and atorvastatin.

10. The compound of formula (I) according to claim 1, which is 2-[2'-(nitroxy)ethyloxy]-ethyl ester pravastatin, fluvastatin and atorvastatin.

11. The compound of formula (I) according to claim 1 for use as a drug having anti-inflammatory, antithrombotic and antiplatelet activity.

12. The use of compounds according to claim 1 for the preparation of a drug having anti-inflammatory, antithrombotic, antithrombotic the ary activity.

13. The use of compounds according to claim 1 for the preparation of a drug for reducing cholesterol and triglyceride levels and/or increase the levels of HDL-C.

14. Pharmaceutical composition having anti-inflammatory, antithrombotic and antiplatelet activity and comprising pharmaceutically acceptable carrier and a pharmaceutically effective amount of the compounds of General formula (I) and/or its salt or stereoisomer according to claim 1.



 

Same patents:

Crystal habits // 2334738

FIELD: chemistry.

SUBSTANCE: invention concerns crystal habits of fluvastatin sodium salt hydrates referred to as polymorphic crystal habits C, D, E and F. Production method of these crystal habits, pharmaceutical composition for 3-hydroxy-3-methylglutaryl- coenzyme YMG-CoA inhibition based on these crystal habits C, D, E, F are described.

EFFECT: production of crystal habits of fluvastatin sodium salt hydrates.

8 cl, 6 dwg, 6 ex

FIELD: organic chemistry, medicine, biochemistry.

SUBSTANCE: invention relates to novel compounds of indoline of the formula (I): , wherein R1 and R3 are similar or different and each means hydrogen atom (H), lower alkyl group or lower alkoxy-group; R2 means -NO2, -NHSO2R6 [wherein R means (C1-C20)-alkyl group, aryl group or -NHR7 (wherein R7 means H, -COR13 (wherein R13 means H, lower alkyl group) or lower alkoxycarbonyl group)], -NHCONH2 or lower alkyl group substituted with -NHSO2R6 [wherein R6 means (C1-C20)-alkyl group, aryl group or -NHR7 (wherein R7 means H, -COR13 (wherein R13 means H, lower alkyl group) or lower alkoxycarbonyl group)]; R4 means H, (C1-C20)-alkyl group optionally substituted with hydroxy-group, -COR13 (wherein R13 means H, lower alkyl group), lower alkenyl group, lower alkoxy-lower alkyl group, lower alkylthio-lower alkyl group, (C3-C8)-cycloalkyl group or (C3-C8)-cycloalkyl-(C1-C3)-alkyl group; R5 means (C1-C20)-alkyl group, (C3-C8)-cycloalkyl group or aryl group; R12 means H, lower alkyl group, lower alkoxy-lower alkyl group or lower alkylthio-lower alkyl group wherein aryl represents phenyl or naphthyl, or its pharmaceutically acceptable salt. Compounds possesses the strong inhibitory effect on activity of acyl-coenzyme A:cholesterol acyltransferase and the strong inhibitory effect on lipid peroxidation processes that allows its using as a component of pharmaceutical compositions.

EFFECT: valuable medicinal and biochemical properties of compound and pharmaceutical compositions.

31 cl, 5 tbl, 68 ex

The invention relates to N-substituted indole-3-glycinamide General formula I, possess Antiasthmatic, antiallergic and immunosuppressive/immunomodulatory action

where R is hydrogen, (C1-C6)alkyl, and the alkyl group optionally contains one phenyl substituent, which, in turn, optionally contains at least one Deputy, selected from the group comprising halogen, methoxy, ethoxy, (C1-C6)alkyl; R1means phenyl cycle containing at least one Deputy, selected from the group comprising (C1-C6)alkoxy, hydroxy, nitro, (C1-C6)alkoxycarbonyl one or fluorine, or R1represents the balance of the pyridine of the formula II

where the carbon atoms 2, 3 and 4 of the remaining pyridine optionally have the same or different substituents R5and R6and R5and R6denote (C1-C6)alkyl or halogen, or R1presents arylamination-2-methylprop-1-ilen group, or R and R1together with the nitrogen atom to which IGN="ABSMIDDLE">

where R7denotes phenyl or pyridinyl; R2means (C1-C6)alkyl, which optionally contains a phenyl residue, which, in turn, optionally substituted with halogen, methoxy group or ethoxypropane, or related to R2(C1-C6)alkyl group optionally substituted 2-, 3 - or 4-pyridinium residue; R3and R4are the same or different substituents and represent hydrogen, hydroxy, (C1-C6)alkoxy, (C1-C3)alkoxycarbonyl or (C1-C3)alkoxycarbonyl(C1-C3)alkyl, or R3is cyclopentanecarbonitrile; Z denotes Oh, and alkyl, alkoxy or alkylamino mean as an unbranched group, such as methyl, ethyl, n-propyl, n-butyl, n-hexyl and branched alkyl groups such as isopropyl or tert-butylene group; halogen means fluorine, chlorine, bromine or iodine and alkoxygroup means methoxy, propoxy, butoxy, isopropoxy, isobutoxy or phenoxypropan, and their pharmaceutically acceptable salts with acids

The invention relates to new hydroxyindole General formula

< / BR>
where R1- C1-C12-alkyl, linear or branched, if necessary monosubstituted monocyclic saturated or polyunsaturated carbocycles with 6 ring members, WITH6-aryl group and closed carbocyclic substituents on its part, if necessary, can be mono - or polyamidine R4; R5- monocyclic polyunsaturated carbocycles with 6 ring members, mono - or politeley atoms, halogen or a monocyclic polyunsaturated heterocycles with 6 ring members, one of which is N as heteroatom, mono - or politeley atoms of halogen; R2and R3can be hydrogen or HE, and at least one or both of the Deputy should be-HE; R4means-H, -OH, -F, -Cl, -J, -Br, -O-C1-C6-alkyl, -NO2; A -, or a bond, or -(CHOZ)m-(C= 0)-, and m= 0

The invention relates to new indole derivative of the formula I

< / BR>
in which R1is hydrogen, (NISS

The invention relates to derivatives of 2-phenylindole, mixtures of their isomers or individual isomers of General formula I, where R1is unbranched or branched C1-C8is alkyl or hydrogen; R2- the remainder of the formula CO-NH2or-CH2-OH

The invention relates to 1H-indol-3-acetamide General formula I where X is oxygen; R1selected from groups (i), (iii), where (i)6-C20-alkyl, C4-C12-cycloalkyl; (iii) - (CH2)n-(R80), where n is 1-8 and R80is the group specified in (i); R2is hydrogen, halogen, C1-C3-alkyl, C1-C2-alkylthio,1-C2-alkoxy; R3each independently is hydrogen or methyl; R4- R7each independently - C1-C10-alkyl, C2-C10alkenyl,3-C8-cycloalkyl,1-C10-alkoxy,

WITH4-C8-cycloalkane, phenoxy, halogen, hydroxy, carboxyl, -C(O)O(C1-C10-alkyl), hydrazide, hydrazino, NH2, NO2, -C(O)NR82R83where R82and R83independently is hydrogen, C1-C10-alkyl or a group of formula (a), where R84and R85independently is hydrogen, C1-C10-alkyl; p= 1 to 5; z is a bond, -O-, -NH-; Q is-CON(R82R83), -SO3H, phenyl, a group of formula b), C), (d), where R86independently selected from hydrogen, C1-C10-alkyl, and their pharmaceutically acceptable salts or their esters, or Amida

Derived indole // 2137759

The invention relates to new compounds of General formula I, where R1-R4is hydrogen, halogen, lower alkyl or trifluoromethyl, R5and R6is hydrogen, halogen, lower alkyl, trifluoromethyl or lower alkoxy and R7- lower alkyl, and pharmaceutically acceptable additive salts of acid compounds of the formula I

FIELD: chemistry.

SUBSTANCE: invention pertains to new method of obtaining phenylamide 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxotetrahydropyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid (I), of the key intermediate compound in the synthesis of atorvastatin calcium, which is a hypolipidemic and/or hypocholesteremic agent. The invention also relates to methods of obtaining intermediate product and to new intermediate products.

EFFECT: perfected method of obtaining phenylamide 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxotetrahydropyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid.

11 cl, 3 ex

The invention relates to new and useful acaricidal and insecticidal arilpirolii compounds, methods for their preparation, intermediate compounds for their production, methods of producing these compounds, and methods of control of ticks and insects

FIELD: medicine; endocrinology.

SUBSTANCE: derivatives of cyanopyrolidines, characterised by the structural formula I, pharmaceutical compositions on their basis or their combination with other hypolipidemic agents are administered in effective doses for lipidemia treatment.

EFFECT: effective correction of lipidemia at the expense of appreciable depression of levels of triglycerides, cholesterol, and low density lipoproteins.

1 ex, 14 cl

FIELD: medicine.

SUBSTANCE: invention concerns a tablet containing fluvastatin with sodium carboxymethylcellulose of calcium in the form of raising agent. The fluvastatin tablet is characterised by time of disintegration from 10 to 30 minutes and good bioavailability equivalent to bioavailability of serially produced capsules, containing fluvastatin. Manufacturing of tablets does peroral application of fluvastatin economically more favourable and more convenient for patients.

EFFECT: rising of profitability and convenience of peroral fluvastatin application to patients.

12 cl, 7 dwg, 6 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: there is offered application of the substance representing enzyme-processed fish protein hydrolyzate able to inhibit activity of acyl-CoA cholesterole acyltransferase and to intensify mitochondrial β-oxidation for making a pharmaceutical or food composition applied for treatment and/or prevention of hepatic adipose degeneration in animals, for treatment and/or prevention of hypercholesterolemia and for treatment and/or prevention of hyperhomocysteinemia, and also for treatment and/or prevention of atherosclerosis, coronary heart disease, stenosis, thrombosis, myocardial infarction and stroke in an animal. There is offered method for making enzyme-processed fish protein hydrolyzate able to inhibit activity of acyl-CoA cholesterole acyltransferase, to reduce triglyceride concentration in liver, to reduce homocysteine concentration in plasma and/or to intensify mitochondrial β-oxidation. The preferential embodiment of the invention concerns FPH application as an antiatherogenic and cardioprotective agent presented either as a pharmaceutical agent, or as a functional food.

EFFECT: improved properties of the substance.

14 cl, 7 ex, 5 tbl, 4 dwg

FIELD: medicine.

SUBSTANCE: method involves products of submerged cultivation of xylotrophic fungi Trametes hirsuta TI-14 or Trametes ochracea TI-15, or Panus conchatiis TI-16, or Cerrena unicolor TI-9, or Ganoderma lucidum TI-7, or Flammulina velutipes TI-3 as a biomass contained in the higher basidiomycetes culture collection of microbiological synthesis department of St.-Petersburg state technical university. The biomass is introduced into the dietary intake in minimal amount 2% of the whole dietary intake.

EFFECT: lower blood level of total cholesterol and triglycerides and lower liver lever of total cholesterol.

2 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical preparation for treatment of hypercholesterolemia and hyperlipemia containing an amorphous active material in inert gas medium. There are disclosed stabilisation method of the pharmaceutical preparation containing pharmaceutical composition with the amorphous active material, stabilisation process of the pharmaceutical composition containing the amorphous active method, and stabilisation method of the amorphous active material. The amorphous active substance may represent amorphous calcium atorvastatin.

EFFECT: improved effectiveness.

25 cl, 3 ex, 4 tbl

FIELD: chemistry, pharmacology.

SUBSTANCE: present invention relates to compounds with formula I, active towards receptors, activated by peroxisome proliferators (PPAR), and can be used in medicine, formula I, where U, W, X and Y represent CH, V represents CR8; R1 represents-C(O)OR or a carboxylic acid isoster, where R is a hydrogen atom, substituted alkyl, aryl or heteroaryl; R2 represents -S(O)2R21; R6 and R7 represent a hydrogen atom, substituted alkyl or cycloalkyl; R8 represents a hydrogen atom, halogen, -OR9, substituted inferior alkyl, cycloalkyl, heterocycloalkyl, phenyl, benzyl, heteroaryl or heteroaralkyl; R9 represents a substituted alkyl or cycloalkyl; R21 represents a substituted heteroaryl or phenyl; n equals 1.

EFFECT: obtaining new biologically active compounds and pharmaceutically active compositions based on these compounds.

46 cl, 134 ex, 4 tbl

FIELD: medicine.

SUBSTANCE: it is offered a cholesterol-regulating medical product intended for normalisation of level of cholesterol. The agent contains a formaldehyde solution and sodium chloride, thereat formaldehyde content makes 0.07-0.24%.

EFFECT: agent for 35 and 65 days of treatment authentically normalised cholesterol level in blood at the moderate and expressed hypercholesterinemia.

3 tbl

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